ES2987429T3 - 4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1-(2h)-carboxamide derivatives as inhibitors of Limk and/or Rock kinases for use in the treatment of cancer - Google Patents

Abstract

The present invention relates to a compound of formula (I), in particular as inhibitors of LIMK and/or ROCK kinases. The present invention also relates to a use of these novel inhibitors in the treatment of a condition selected from the group consisting of: cancers, virus infections, ocular hypertension and glaucoma formation, neurofibromatosis type 1 and 2, psoriatic lesions, inflammatory diseases and hyperalgesia, central sensitization and chronic pain, reproductive erectile dysfunction and neuronal diseases. The present description discloses the synthesis and characterization of exemplary compounds, as well as pharmacological data thereof (e.g., pages 37 to 163; examples 1 to 169; compounds; biological studies; tables; pages of figures 1/6 to 6/6). An exemplary compound is, for example, 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-phenyl-3,6-dihydropyridine-1-(2H)-carboxamide (Example 1; Compound 5). (Automatic translation with Google Translate, no legal value)

Description

DESCRIPTION

4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1-(2h)-carboxamide derivatives as inhibitors of Limk and/or Rock kinases for use in the treatment of cancer

The present invention relates to novel inhibitors of LIMK and/or ROCK kinases and therapeutic uses thereof. The present invention also relates to these novel inhibitors as anticancer agents.

LIM kinases (LIMKs) are serine/threonine and tyrosine kinases involved in the regulation of cytoskeletal dynamics. They phosphorylate cofilin, resulting in its inhibition (Scott, R. W. and Olson, M. F. (2007) LIM kinases: function, regulation and association with human disease. Journal of molecular medicine (Berlin, Germany). 85, 555-568). Cofilin is a member of the actin depolymerizing factor (ADF) family and regulates actin polymerization dynamics by promoting rapid turnover of actin filaments (Bamburg, J. R. and Bernstein, B. W. (2010) Roles of ADF/cofilin in actin polymerization and beyond. F1000 biology reports. 2, 62; Mizuno, K. (2013) Signaling mechanisms and functional roles of cofilin phosphorylation and dephosphorylation. Cellular signalling. 25, 457-469; Pollard, T. D. and Borisy, G. G. (2003) Cellular motility driven by assembly and disassembly of actin filaments. Cell. 112, 453-465). LIMKs also control microtubule dynamics, independent of their regulation of actin remodeling. The molecular mechanism by which LIMKs regulate microtubule dynamics is still unknown (Prunier, C., Prudent, R., Kapur, R., Sadoul, K., & Lafanechere, L. (2017) LIM kinases: cofilin and beyond. Oncotarget. 8, 41749-41763). Therefore, LIMKs play a crucial role in cytoskeletal remodeling, contributing to many cellular functions such as cell motility, morphogenesis, division, differentiation, apoptosis, neuronal morphology, neuritogenesis and oncogenesis.

The LIMK family consists of only two members: LIMK1 and LIMK2. Recently, LIMKs have emerged as new therapeutic targets, as they have been shown to be involved in many diseases, for example, in numerous types of cancer, in viral infections, in ocular hypertension and in the formation of glaucoma. They also play a role in neurofibromatosis type 1 and 2 (NF1 and NF2). LIMKs are also involved in psoriatic lesions, in the inflammatory response, in the development of inflammatory hyperalgesia, central sensitization and chronic pain, in oocyte maturation and in erectile dysfunction due to old age. More recently, LIMKs have been shown to play a key role in neuronal development and plasticity, they are involved in several neuronal diseases such as amyotrophic lateral sclerosis, Parkinson's and Alzheimer's diseases, Williams-Beuren syndrome, schizophrenia, intellectual disability...

Rho-associated coiled-coil-containing kinases (ROCKs) are serine/threonine kinases, members of the AGC kinase family (Hartmann, S.; Ridley, A. J.; Lutz, S. The Function of Rho-Associated Kinases ROCK1 and ROCK2 in the Pathogenesis of Cardiovascular Disease. Front. Pharmacol. 2015, 6, 276). ROCKs phosphorylate several targets: 1/Myosin Light Chain (MLC) together with Myosin Light chain Phosphatase (MLCP) thereby inactivating this later and allowing MLC phosphorylation to persist (Amano, M.; Nakayama, M.; Kaibuchi, K. Rho-kinase /ROCK: A key regulation of the cytoskeleton and cell polarity. Cytoskeleton 2010, 67, 545-554). This results in stimulation ofACTOMYOSIN contractility and cell contraction. 2/ LIMK2 which becomes activated and phosphorylates cofilin leading to the inactivation of this latter and actin filament stabilization (Maekawa, M.; Ishizaki, T.; Boku, S.;Watanabe, N.; Fujita, A.; Iwamatsu, A. ; Obinata, T.; Ohashi, K.; Narumiya, S. Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. Science 1999, 285, 895-898). 3/ Ezrin, radixin and moesin (ERM), which are involved in actin/plasma membrane interactions (Matsui, T.; Maeda, M.; Doi, Y.; Yonemura, S.; Amano, M.; Kaibuchi, K. ; Tsukita, S.; Tsukita, S. Rho-kinase phosphorylates COOH-terminal threonines of ezrin/radixin/moesin (ERM) proteins and regulates their head-to-tail association. J. Cell Biol. 1998, 140, 647-657). 4/ Collapsin response mediator protein-2 (CRMP-2), thereby inhibiting its ability to stimulate microtubule assembly and axonal growth (Arimura, N.; Menager, C.; Fukata, Y.; Kaibuchi, K. Role of CRMP-2 in neuronal polarity. J. Neurobiol.

2004, 58, 34-47). 5/ PTEN (phosphatase and tension homolog), a tumor suppressor thereby preventing it to inhibit cell growth and survival (Li, Z.; Dong, D.;Wang, Z.; Liu, W.; Deng, N.; Ding, Y.; Tang, L.; Hla, T.; Li, L.; Regulation of PTEN by Rho small GTPases. 399-404).

Together, these actions play a role in actin cytoskeleton remodeling, cell contractility, and cell death. Consequently, ROCKs regulate different cellular functions such as growth, apoptosis, migration, and metabolism.

ROCKs are involved in different pathologies: heart diseases such as cardiac fibrosis, cardiac hypertrophy, systemic blood pressure disorders, pulmonary hypertension, renal pathologies such as hypertensive nephropathy, Bartter and Gitelman syndrome, diabetic nephropathy, asthma, chronic obstructive pulmonary diseases, traumatic brain injuries, Alzheimer's and Parkinson's diseases, obesity, diabetes mellitus, cancers and autoimmune diseases (lupus erythematosus, rheumatoid arthritis).

BRYCE A. HARRISON ET AL: (“Discovery and Development of LX7101, a Dual LIM-Kinase and ROCK Inhibitor for the Treatment of Glaucoma” , ACS MEDICINAL CHEMISTRY LETTERS, vol. 6, no. 1, December 9, 2014 (09-12 2014), pages 84-88, ISSN: 1948-5875, DOI: 10.1021/ml500367g) describes, for example, 4-(7Hpyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl-carboxamide derivatives (D1: e.g., page 86, Table 3, compounds 1, 11, 13 to 15), as well as a derivative of 4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-1-yl-carboxamide (D1: e.g. page 86, table 3, compound 12) with dual LIMK and ROCK kinase inhibitory activity for use in the treatment of, e.g., glaucoma, ocular hypertension and/or intraocular hypertension.

The objective of the present invention is to provide new small molecules with an inhibitory activity against LIm K and/or ROCK kinases.

The objective of the present invention is to provide new inhibitors of LIMK and/or ROCK kinases.

Another objective of the present invention is to provide new inhibitors of LIMK and ROCK kinases.

Another objective of the present invention is to provide new potent inhibitors targeting both LIMK and ROCK or specific to LIMK depending on the target disease.

Another objective of the present invention is to provide new small molecules as inhibitors of LIMK and/or ROCK kinases, said molecules having a wide range of cytotoxicity, from low toxicity to high toxicity according to potent applications.

Therefore, the present invention relates to a compound having the following formula (I):

where:

- “a” is a single bond and “b” is a double bond, or “a” is a double bond and “b” is a single bond; - R<1> is selected from the group consisting of: H, alkyl group (C<1>-C<6>), halogen and cycloalkyl group (C<3>-C<7>); - R<2> is selected from the group consisting of: H and an alkyl group (C<1>-C<6>);

- or R<1>and R<2>can form together with the carbon atoms that carry them a cycloalkyl group (C<5>-C<7>) or a heterocycloalkyl group (C<5>-C<7>), said heterocycloalkyl group being optionally substituted with an alkyl group (C<1>-C<6>);

- n is 0, 1 or 2 ;

- each R<i>, identical or different, is selected from the alkyl groups (C<1>-C<6>);

- R is selected from the group consisting of: cycloalkyl group (C<3>-C<7>), optionally fused with an aryl group, aryl group, heteroaryl group, heterocycloalkyl group fused with an aryl group and aryl group fused with a heterocycloalkyl group, said aryl and heteroaryl groups being optionally substituted with at least one substituent R<3> selected from the group consisting of:

. H,

. (C<1>-C<6>)alkyl, said alkyl being optionally interrupted with at least one heteroatom,

. heterocycloalkyl,

. aryl, said aryl being optionally substituted with at least one substituent such as:

. alkoxy (C<1>-C<6>);

. NR<a>R<b>, R<a>and R<b>, independently of each other, where H is an alkyl group (C<1>-C<6>);

. -X-R<c>, where X is a bond, an alkylene group (C<1>-C<6>), preferably -CH<2>-, or -C(=O)-, and where R<c> is a heterocycloalkyl group, optionally substituted with at least one alkyl group (C<1>-C<6>), SO<2>CH<3>, or an alkylamino group (C<1>-C<6>);

. halogen;

. -C(=O)-NR<a>R<b>, R<a>and R<b>, independently of each other, where H is an alkyl group (C<1>-C<6>);

. --C(=O)-N(R<d>)-X<1>-NR<a>R<b>, R<d>, R<a>and R<b>, independently of each other, where H is an alkyl group (C<1>-C<6>), and where X<1> is an alkylene group (C<1>-C<6>), preferably CH<2>; or

. -O-X<2>-NR<e>R<f>, where X<2> is an alkylene group (C<1>-C<6>), R<e>and R<f>, independently of each other, where H is or an alkyl group (C<1>-C<6>), or at least one of the groups R<e>and R<f>, is an amino acid protecting group such as a carbamate (Boc) or comprises a fluorophore such as difluoroborane; or

. heteroaryl, said heteroaryl being optionally substituted with at least one substituent such as:

. alkoxy (C<1>-C<6>);

. NR<a>R<b>, R<a>and R<b>, independently of each other, where H is an alkyl group (C<1>-C<6>);

. -C(=O)-NR<a>R<b>, R<a>and R<b>, independently of each other, where H is an alkyl group (C<1>-C<6>); or

. -NH-C(=O)-R<a>, where R<a>H or an alkyl group (C<1>-C<6>);

. halogen,

. haloalkyl (C<1>-C<6>),

. aryloxy, said aryloxy being optionally substituted with at least one substituent such as:

. alkoxy (C<1>-C<6>);

. NR<a>R<b>, R<a>and R<b>, independently of each other, where H is an alkyl group (C<1>-C<6>);

. -X-R<c>, where X is a bond, an alkylene group (C<1>-C<6>), preferably -CH<2>-, or -C(=O)-, and where R<c> is a heterocycloalkyl group, optionally substituted with at least one alkyl group (C<1>-C<6>), SO<2>CH<3>, or an alkylamino group (C<1>-C<6>);

. halogen;

-C(=O)-NR<a>R<b>, R<a>and R<b>, independently of each other, where H is an alkyl group (C<1>-C<6>); or

. -C(=O)-N(R<d>)-X<1>-NR<a>R<b>, R<d>, R<a>and R<b>, independently of each other, where H is an alkyl group (C<1>-C<6>), and where X<1> is an alkylene group (C<1>-C<6>), preferably CH<2>;

. -O-haloalkyl (C<1>-C<6>),

. cyan,

. alkoxy (C<1>-C<6>), and

. -X-NR<a>R<b>, where X is selected from the group consisting of: alkylene group (C<1>-C<6>), -O-C(=O)-, -C(=O)-, and -NH-C(=O)-, and R<a>and R<b>, independently of each other, where H is an alkyl group (C<1>-C<6>);

or their pharmaceutically acceptable salts, racemates, diastereomers or enantiomers.

The present invention relates to a compound having the following formula (I):

where:

- “a” is a single bond and “b” is a double bond, or “a” is a double bond and “b” is a single bond; - R<i>is selected from the group consisting of: H, alkyl group (C<1>-C<6>), halogen and cycloalkyl group (C<3>-C<7>); - R<2>is selected from the group consisting of: H and an alkyl group (C<1>-C<6>);

- or R<1>and R<2>can form together with the carbon atoms that carry them a cycloalkyl group (C<5>-C<7>) or a heterocycloalkyl group (C<5>-C<7>), said heterocycloalkyl group being optionally substituted with an alkyl group (C<1>-C<6>);

- n is 0, 1 or 2 ;

- each R<i>, identical or different, is selected from the alkyl groups (C<1>-C<6>);

- R is selected from the group consisting of: cycloalkyl group (C<3>-C<7>), optionally fused with an aryl group, aryl group, heteroaryl group, heterocycloalkyl group fused with an aryl group and aryl group fused with a heterocycloalkyl group, said aryl and heteroaryl groups being optionally substituted with at least one substituent R<3> selected from the group consisting of:

. H,

. (C<1>-C<6>)alkyl, said alkyl being optionally interrupted with at least one heteroatom,

. heterocycloalkyl,

. aryl, said aryl being optionally substituted with at least one substituent such as:

. alkoxy (C<1>-C<6>);

. NR<a>R<b>, R<a>and R<b>, independently of each other, where H is an alkyl group (C<1>-C<6>);

. -X-R<c>, where X is a bond, an alkylene group (C<1>-C<6>), preferably -CH<2>-, or

-C(=O)-, and Rc being a heterocycloalkyl group, optionally substituted with at least one alkyl group (C<1>-C<6>), SO<2>CH<3> or an alkylamino group (C<1>-C<6>);

. halogen;

. -C(=O)-NR<a>R<b>, R<a>and R<b>, independently of each other, where H is an alkyl group (C<1>-C<6>);

. -C(=O)-N(R<d>)-X<1>-NR<a>R<b>, R<d>, R<a>and R<b>, independently of each other, where H is an alkyl group (C<1>-C<6>), and where X<1> is an alkylene group (C<1>-C<6>), preferably CH<2>; or

. -O-X<2>-NR<e>R<f>, where X<2> is an alkylene group (C<1>-C<6>), R<e>and R<f>, independently of each other, where H is or an alkyl group (C<1>-C<6>), or at least one of the groups R<e>and R<f>, is an amino acid protecting group such as a carbamate or comprises a fluorophore or is SO<2>CH<3>; or

. heteroaryl, said heteroaryl being optionally substituted with at least one substituent such as:

. alkoxy (C<1>-C<6>);

. NR<a>R<b>, R<a>and R<b>, independently of each other, where H is an alkyl group (C<1>-C<6>);

. -C(=O)-NR<a>R<b>, R<a>and R<b>, independently of each other, where H is an alkyl group (C<1>-C<6>); or

. -NH-C(=O)-R<a>, where R<a>H or an alkyl group (C<1>-C<6>);

. halogen,

. haloalkyl (C<1>-C<6>),

. aryloxy, said aryloxy being optionally substituted with at least one substituent such as:

. alkoxy (C<1>-C<6>);

. OH;

. NR<a>R<b>, R<a>and R<b>, independently of each other, where H is an alkyl group (C<1>-C<6>);

. -X-R<c>, where X is a bond, an alkylene group (C<1>-C<6>), preferably -CH<2>-, or

-C(=O)-, and Rc being a heterocycloalkyl group, optionally substituted with at least one alkyl group (C<1>-C<6>), SO<2>CH<3> or an alkylamino group (C<1>-C<6>);

. halogen;

. -O-benzyl,

. -O-C(=O)-NR<a>R<b>, R<a>and R<b>, independently of each other, where H is an alkyl group (C<1>-C<6>);

. -NH-C(=O)-R<a>, where R<a>H or an alkyl group (C<1>-C<6>);

. -C(=O)-NR<a>R<b>, R<a>and R<b>, independently of each other, where H is an alkyl group (C<1>-C<6>); or

. -C(=O)-N(R<d>)-X<1>-NR<a>R<b>, R<d>, R<a>and R<b>, independently of each other, where H is an alkyl group (C<1>-C<6>), and where X<1> is an alkylene group (C<1>-C<6>), preferably CH<2>;

. heteroaryloxy, said heteroaryloxy being optionally substituted with at least one substituent such as: -O-C(=O)-NR<a>R<b>, R<a>and R<b>, independently of each other, where H is an alkyl group (C<1>-C<6>);

. -O-haloalkyl (C<1>-C<6>),

. cyan,

. alkoxy (C<1>-C<6>),

. -X-NR<a>R<b>, where X is selected from the group consisting of: alkylene group (C<1>-C<6>), -O-C(=O)-, -C(=O)-, and -NH-C(=O)-, and R<a>and R<b>, independently of each other, where H is an alkyl group (C<1>-C<6>);

. -X'-R<c>, where X' is -C (=O) - or an alkylene radical -O-(C<1>-C<6>), where R<c> is a cycloalkyl group, optionally substituted with at least one halogen, or where R<c> is a heterocycloalkyl group, optionally substituted with SO<2>CH<3> or at least one alkyl group (C<1>-C<6>); and

. -O-X<2>-NR<e>R<f>, where X<2> is an alkylene group (C<1>-C<6>), R<e>and R<f>, independently of each other, where H is an alkyl group (C<1>-C<6>), or at least one of the groups R<e>and R<f>, is an amino acid protecting group such as a carbamate (Boc);

or their pharmaceutically acceptable salts, racemates, diastereomers or enantiomers.

According to one embodiment, in formula (I), R is a (C<3>-C<7>)cycloalkyl group, preferably an unsubstituted cyclohexyl group.

According to another embodiment, in formula (I), R is an aryl group, optionally substituted with at least one R<3> substituent as defined above, and is preferably an optionally substituted phenyl group as defined above.

According to one embodiment, when R is an aryl group, preferably a phenyl group, substituted with at least one substituted aryl group, preferably a substituted phenyl group, the following R groups may be mentioned:

According to one embodiment, in formula (I), R is an aryl group, preferably a phenyl group, substituted with at least one aryl group, preferably a phenyl group, substituted with a group -O-X2-NReRf as defined above.

Preferably, in this embodiment, the group -O-X<2>-NR<e>R<f>is selected from the following groups: O-X<2>-NHBoc, preferably -O-(CH<2>)<3>-NHBoc, -O-X<2>-NH-C(=O)alkyl, preferably -O-(CH<2>)<a>-NH-C(=O)Me, -O-X<2>-NH-SO<2>-alkyl, preferably -O-(CH<2>)<3>-NH-SO<2>-Me, group -O-X<2>-NR<e>R<f>wherein R<e>and R<f>are alkyl groups, preferably methyl, and the group having the following formula:

According to one embodiment, at least one of Re and Rf is an amino protecting group, such as a carbamate (Boc), or comprises a fluorophore, such as difluoroborane derivatives. As difluoroborane derivatives, there may be mentioned the fluorophore 5,5-difluoro-1,3-dimethyl-5H-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinine.

According to this embodiment, the following compounds can be mentioned:

According to one embodiment, when R is an aryl group, preferably a phenyl group, substituted with at least one substituted heteroaryl group, the following R groups may be mentioned:

The following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.

The expression “C<t>-C<z>” means a carbon-based chain that may have t to z carbon atoms, for example, C<1>-C<3> means a carbon-based chain that may have 1 to 3 carbon atoms.

The term “alkyl group” means: a linear or branched, saturated, hydrocarbon-based aliphatic group comprising, unless otherwise stated, 1 to 12 carbon atoms. By way of example, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tert-butyl or pentyl groups may be mentioned.

The term “aryl group” means: a cyclic aromatic group comprising between 6 and 10 carbon atoms. Examples of aryl groups include phenyl or naphthyl groups.

The term "heteroaryl group" means: a 5- to 10-membered monocyclic or bicyclic aromatic group containing 1 to 4 heteroatoms selected from O, S or N. By way of example, imidazolyl, thiazolyl, oxazolyl, furanyl, thiophenyl, pyrazolyl, oxadiazolyl, pyridinyl, thiophenyl, pyrazolyl, oxadiazolyl, pyridinyl, razinyl, pyrimidinyl, pyridazinyl, indolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzimidazolyl, indazolyl, benzothiazolyl, isobenzothiazolyl, benzotriazolyl, quinolinyl and isoquinolinyl groups.

By way of a heteroaryl comprising 5 to 6 atoms, including 1 to 4 nitrogen atoms, the following representative groups may be mentioned in particular: pyrrolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl and 1,2,3-triazinyl.

Also mentioned as heteroaryl are thiophenyl, oxazolyl, furazanyl, 1,2,4-thiadiazolyl, naphthyridinyl, quinoxalinyl, phthalazinyl, imidazo[1,2-a]pyridine, imidazo[2,1-b]thiazolyl, cinnolinyl, benzofurazanyl, azainyl, dolyl, benzimidazolyl, benzothiophenyl, thienopyridyl, thienopyrimidinyl, pyrrolopyridyl, imidazopyridyl, benzoazaindole, 1,2,4-triazinyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, purinyl, quinazolinyl, isoquinolyl, 1,3,4-thiadiazolyl, thiazolyl, isothiazolyl, carbazolyl and also the corresponding groups resulting from their fusion with the phenyl nucleus.

The term “heterocycloalkyl group” means: a saturated or partially unsaturated 4- to 10-membered monocyclic or bicyclic group comprising one to three heteroatoms selected from O, S or N; the heterocycloalkyl group may be linked to the remainder of the molecule through a carbon atom or through a heteroatom; the term bicyclic heterocycloalkyl includes fused bicycles and spiral type rings.

As saturated heterocycloalkyl comprising 5 to 6 atoms, mention may be made of oxetanyl, tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, azepinyl, oxazepinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, dithiolanyl, thiazolidinyl, tetrahydropyriranyl, tetrahydropyriranyl, tetrahydropyridinyl dinyl, dioxanyl, morpholinyl, piperidinyl, piperazinyl, tetrahydrothiopyranyl, dithianyl, thiomorpholinyl or isoxazolidinyl.

Among the heterocycloalkyls, there may also be mentioned, by way of example, bicyclic groups such as (8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, octahydroindozylinyl, diazepanyl, dihydroimidazopyrazinyl and diazabicycloheptanyl, or diazaspiro rings such as 1,7-diazaspiro[4.4]non-7-yl or 1-ethyl-1,7-diazaspiro[4.4]non-7-yl.

When heterocycloalkyl is substituted, the substitution(s) may be on one (or more) carbon atom(s) and/or on the heteroatom(s). When heterocycloalkyl comprises several substituents, they may be carried by the same atom or by different atoms.

The term “cycloalkyl group” means: a carbon-based cyclic group comprising, unless otherwise stated, 3 to 6 carbon atoms. By way of example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. groups may be mentioned.

When an alkyl radical is substituted by an aryl group, the term “arylalkyl” or “aralkyl” radical is used. “Arylalkyl” or “aralkyl” radicals are aryl-alkyl radicals, the aryl and alkyl groups being those defined above. Among the arylalkyl radicals, mention may in particular be made of the benzyl or phenethyl radicals.

The term “halogen” means: a fluorine, a chlorine, a bromine or an iodine.

The term “alkoxy group” means: an -O-alkyl radical where the alkyl group is as defined above. By way of example, there may be mentioned the -O-(C<1>-C<4>) alkyl groups, and in particular the -O-methyl group, the -O-ethyl group as the -O-C-alkyl group, the -O-propyl group, the -O-isopropyl group and as the -O-C<4> alkyl group, the -O-butyl, -O-isobutyl or -O-tert-butyl group.

The “alkyl”, “cycloalkyl”, “aryl”, “heteroaryl” and “heterocycloalkyl” radicals mentioned above may be substituted with one or more substituents. Among these substituents, the following groups may be mentioned: amino, hydroxyl, thiol, oxo, halogen, alkyl, alkoxy, alkylthio, alkylamino, aryloxy, arylalkoxy, cyano, trifluoromethyl, carboxyl or carboxyalkyl.

The term “alkylthio” means: an -S-alkyl group, the alkyl group being as defined above.

The term “alkylamino” means: an -NH-alkyl group, the alkyl group being as defined above. The term “aryloxy” means: an -O-aryl group, the aryl group being as defined above.

The term “arylalkoxy” means: an aryl-alkoxy group, the aryl and alkoxy groups being as defined above. The term “carboxyalkyl” means: an HOOC-alkyl group, the alkyl group being as defined above. As examples of carboxyalkyl groups, mention may in particular be made of carboxymethyl or carboxyethyl.

The term “haloalkyl group” means: an alkyl group as defined above, in which one or more of the hydrogen atoms are (are) replaced by a halogen atom. By way of example, mention may be made of fluoroalkyls, in particular CF<3> or CHF<2>.

The term “carboxyl” means: a COOH group.

The term “oxo” means: “=O”.

In some embodiments of the invention, the compounds of the invention may contain one or more asymmetric centers and therefore occur as racemates and racemic mixtures, single enantiomers, single diastereomeric mixtures. All such isomeric forms of these compounds are included in the present invention, unless otherwise expressly indicated.

In some embodiments, the compounds of the invention may contain one or more double bonds and therefore occur as individual isomers or mixtures of Z and/or E isomers. All such isomeric forms of these compounds are included in the present invention, unless expressly indicated otherwise.

In embodiments where the compounds of the invention may contain multiple tautomeric forms, the present invention also includes all tautomeric forms of said compounds, unless expressly stated otherwise.

A preferred family of compounds according to the invention are those compounds having the following formula (II):

where:

- a, b, n, R<i>, R<1>, and R<2>are as defined above in formula (I), and

- m is 1 or 2, and each R<3>, identical or different, is as defined in formula (I).

Compounds of formula (II) are compounds of formula (I) wherein R is a phenyl group, substituted with at least one R<3> group.

A preferred family of compounds according to the invention are those compounds having the following formula (III):

where:

- a, b, n, R<i>, R<1>, R<2>, and R<3>are as defined above in formula (I), and

- R<4>is H, halogen or aryloxy.

A preferred family of compounds according to the invention are those compounds having the following formula (IV):

where:

- R<1> is H or an alkyl group (C<1>-C<6>);

- R<3>is selected from the group consisting of:

• H,

• alkyl (C<1>-C<6>),

• aryl, preferably phenyl, said aryl being optionally substituted with at least one substituent such as (C<1>-C<6>) alkoxy, in particular OMe, or halogen such as F,

• heteroaryl, such as pyridinyl, imidazolyl, pyrrolyl or triazolyl,

• halogen, such as F, Cl or Br,

• haloalkyl (C<1>-C<6>), such as CF<3>,

• aryloxy, in particular phenyloxy, said aryloxy being optionally substituted with at least one substituent such as (C<1>-C<6>)alkoxy, preferably OMe,

• -O-haloalkyl (C<1>-C<6>), such as OCF<3>,

• cyan,

• alkoxy (C<1>-C<6>), such as OMe, and

• -O-C(=O)-NR<a>R<b>, R<a>and R<b>, independently of each other, where H is an alkyl group (C<1>-C<6>); and

- R<4>is H, halogen or aryloxy, such as phenyloxy,

or R<3>and R<4>form together with the carbon atoms that carry them a phenyl group or a heterocycloalkyl group preferably comprising 2 oxygen atoms and 3 carbon atoms.

Preferably, in formula (IV), R<1>is methyl.

Preferred compounds of formula (IV) are as follows:

A preferred family of compounds according to the invention are the compounds having the following formula (V):

where:

- “a” is a single bond and “b” is a double bond, or “a” is a double bond and “b” is a single bond; - R<1> is an alkyl group (C<1>-C<6>), preferably methyl;

- R<5> is an alkyl group (C<1>-C<6>), preferably methyl;

- R<6>is H or an alkyl group (C<1>-C<6>), preferably methyl;

- R<3>is selected from the group consisting of:

• halogen, such as F, Cl or Br, and

• aryloxy, in particular phenyloxy.

Preferably, in formula (V), R<1>is methyl.

The preferred compounds of formula (V) are the following:

A preferred family of compounds according to the invention are compounds having the following formula (VI):

where R3 is halogen.

A preferred compound of formula (VI) is as follows:

A preferred family of compounds according to the invention are the compounds having the following formula (VII):

where:

- R1 is halogen, preferably Cl; and

- R3 is -O-C(=O)-NRaRb, Ra and Rb, independently of each other, being H or an alkyl group (C1-C6).

A preferred compound of formula (VII) is as follows:

A preferred family of compounds according to the invention are compounds having the following formula (VIII):

where:

- R<1> is a cycloalkyl group (C<3>-C<7>), preferably cyclopropyl;

- R<3>is selected from the group consisting of:

• aryl, preferably phenyl, said aryl being optionally substituted with at least one substituent such as (C<1>-C<6>)alkoxy, in particular OMe,

• heteroaryl, such as pyrrolyl,

• halogen, such as F, Cl or Br,

• aryloxy, in particular phenyloxy, said aryloxy being optionally substituted with at least one substituent such as (C<1>-C<6>)alkoxy, preferably OMe, and

• -O-C(=O)-NR<a>R<b>, R<a>and R<b>, independently of each other, where H is an alkyl group (C<1>-C<6>).

Preferably, in formula (VIII), R<1>is cyclopropyl.

Preferred compounds of formula (VIII) are as follows:

A preferred family of compounds according to the invention are compounds having the following formula (IX):

where:

- R<i>is an alkyl group (C<1>-C<6>), preferably methyl;

- R<2> is an alkyl group (C<1>-C<6>), preferably methyl;

- R<3>is selected from the group consisting of:

• H,

• aryl, preferably phenyl, said aryl being optionally substituted with at least one substituent such as (C<1>-C<6>)alkoxy, in particular OMe,

• halogen, such as F, Cl or Br,

• alkoxy (C<1>-C<6>), such as OMe, and

• -O-C(=O)-NR<a>R<b>, R<a>and R<b>, independently of each other, where H is an alkyl group (C<1>-C<6>).

Preferably, in formula (IX), R<1>and R<2>are identical. More preferably, they are methyl.

Preferred compounds of formula (IX) are as follows:

A preferred family of compounds according to the invention are compounds having the following formula (X):

where:

- p is 0, 1 or 2;

- R3 is selected from the group consisting of:

• H,

• (C1-C6)alkyl, said alkyl being optionally interrupted with at least one heteroatom,

etherocycloalkyl, such as morpholinyl,

aryl, preferably phenyl, said aryl being optionally substituted with at least one substituent such as (C1-C6)alkoxy,

heteroaryl, such as pyridinyl,

halogen,

aryloxy,

haloalkyl (C1-C6),

cyan,

alkoxy (C<1>-C<6>), and

-X-NR<a>R<b>, where X is selected from the group consisting of: alkylene group (C<1>-C<6>), -O-C(=O)-, -C(=O)-, and -NH-C(=O)-, and R<a>and R<b>, independently of each other, where H is an alkyl group (C<1>-C<6>).

Preferred compounds of formula (X) are as follows:

A preferred family of compounds according to the invention are compounds having the following formula (XI):

where:

- - X<1> is -O-, -S- or -N(alkyl (C<1>-C<6>))-, such as -N(Me)-; and

- R<3>is halogen.

Preferred compounds of formula (XI) are as follows:

A preferred family of compounds according to the invention are the compounds having the following formula (XII):

where R<1>and R<2>are as defined above in formula (I).

Preferably, in formula (XII), R<1> is a (C<1>-C<6>) alkyl group, such as methyl or ethyl, or a (C<3>-C<7>) cycloalkyl group, such as cyclopropyl.

Preferably, in formula (XII), R<2> is H or a (C<1>-C<6>) alkyl group, such as ethyl.

Preferred compounds of formula (XII) are as follows:

A preferred family of compounds according to the invention are those compounds having the following formula (XIII):

where R<1>and R<2>are as defined above in formula (I).

Preferably, in formula (XIII), R<1> is a (C<1>-C<6>) alkyl group, such as methyl or ethyl, or a (C<3>-C<7>) cycloalkyl group, such as cyclopropyl.

Preferably, in formula (XIII), R<2> is H or a (C<1>-C<6>) alkyl group, such as ethyl.

The preferred compounds of formula (XIII) are as follows:

The present invention also relates to a medicament comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.

The present invention also relates to a medicament comprising a compound of formula (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII) or (XIII) as defined above, or a pharmaceutically acceptable salt thereof.

The present invention also relates to a pharmaceutical composition, comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, and also at least one pharmaceutically acceptable excipient.

The present invention also relates to a pharmaceutical composition comprising a compound of formula (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII) or (XIII) as defined above, or a pharmaceutically acceptable salt thereof, and also at least one pharmaceutically acceptable excipient.

These excipients are selected, depending on the pharmaceutical form and the desired mode of administration, from among the usual excipients known to those skilled in the art.

The present invention relates to a compound of formula (I) as defined above, or to an addition salt of this compound with a pharmaceutically acceptable acid, for use as a medicament.

The present invention relates to a compound of formula (I) as defined above, or to a pharmaceutically acceptable salt of this compound, for use as a drug.

The present invention also relates to a compound of formula (I) as defined above, or of formula (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII) or (XIII) as defined above, for use in a method of treating a condition selected from the group consisting of cancers, such as breast, lung, pancreas, prostate, colorectal cancers, leukemias, gliomas, melanomas and osteosarcomas, virion infections (HIV, Ebola and herpes viruses...), ocular hypertension and glaucoma formation, neurofibromatosis type 1 and 2 (NF1 and NF2), psoriatic lesions, inflammatory diseases and hyperalgesia, central sensitization and chronic pain, reproductive erectile dysfunction (oocyte maturation) and neuronal diseases such as amyotrophic lateral sclerosis, Parkinson's and Parkinson's diseases. Alzheimer's, Williams-Beuren syndrome, schizophrenia and intellectual disability.

Therefore, the present invention also relates to a compound as defined above for use in a method of treating a condition as defined above.

The present invention also relates to a compound of formula (I) as defined above, or of formula (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII) or (XIII) as defined above, for use in the treatment of cancer.

The present invention also relates to a method of treating the pathological conditions indicated above, comprising administering, to a patient, an effective dose of a compound according to the invention, or a pharmaceutically acceptable salt thereof.

Therefore, the compounds of the invention can be used to treat various pathologies involved in the regulation of cytoskeletal dynamics, cytoskeletal remodeling, cell motility, morphogenesis, division, differentiation, apoptosis, neuronal morphology, neuritogenesis and oncogenesis.

This includes: cancers such as breast, lung, pancreas, prostate, colorectal, leukemia, gliomas, melanomas and osteosarcomas, virion infections (HIV, Ebola and herpes virus...), ocular hypertension and glaucoma formation, neurofibromatosis type 1 and 2 (NF1 and NF2), psoriatic lesions, inflammatory diseases and hyperalgesia, central sensitization and chronic pain, reproduction (oocyte maturation), erectile dysfunction and neuronal diseases such as amyotrophic lateral sclerosis, Parkinson's and Alzheimer's diseases, Williams-Beuren syndrome, schizophrenia, intellectual deficiency.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of the above formula (I), or the salt thereof, may be administered in unitary administration form, as a mixture with conventional pharmaceutical excipients, to animals and humans for the treatment of the above-mentioned disorders and diseases.

Suitable unit administration forms include oral forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular and intranasal administration forms, inhalation administration forms, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants. For topical application, the compounds according to the invention may be used in creams, gels, ointments or lotions.

According to current practice, the physician determines the appropriate dosage for each patient based on the mode of administration and the patient's weight and response.

Examples

Chemical synthesis

General procedure A: Formation of hydrazone

To a suspension of 4-hydroxy-6-hydrazinylpyrimidine (1.0 equiv.) in EtOH (0.5 M) was added corresponding ketone (1.5 equiv.). The reaction was heated at reflux for 3 h and then cooled to 0 °C. The solid was collected by filtration, washed with Et<2>O and dried under high vacuum to afford the desired product.

General procedure B: Fischer synthesis

A suspension of hydrazone (1.0 equiv.) in tetralin (0.25 M) was heated to 260 °C in a sealed tube for 3 h. The reaction mixture was cooled to room temperature. The solid was collected by filtration, washed with petroleum ether and Et<2>O several times, and dried under high vacuum to afford the desired product.

General procedure C: Chlorination

A solution of the tricyclic compound (1.0 equiv.) in POCb (0.15 M) was heated at 100 °C for 1 h. Excess POCl<a> was removed in vacuo and the resulting dark suspension was taken up in CH<2>Cfc and poured into an ice bath. The mixture was stirred for 1 h and extracted with CH<2>Ch. The organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford the desired product.

General procedure D: Suzuki-Miyaura cross coupling

To a solution of the chlorinated heterocycle (1.0 equiv.) in THF (0.25 M) was added boronate ester (1.1 equiv.) followed by a 2 M aqueous solution of Na2CO3 (3.0 equiv.). The solution was degassed for 20 min with argon and Pd(PPh3)4 (0.1 equiv.) was added. The mixture was then heated under microwave irradiation at 120 °C for 1.5 h, cooled and extracted with CH<2>Ch. The organic phases were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford the desired product. General Procedure E: Hydrogenation

Pd/C (10 wt%) was added (0.05 equiv.) to a solution of N-protected compound (1.0 equiv.) in MeOH (0.06 M). The reaction was stirred under H<2>pressure until completion. The mixture was filtered through a pad of Celite which was rinsed several times with MeOH. The MeOH was evaporated under reduced pressure and the crude reaction mixture was used in the next step without further purification.

General procedure F1: Boc deprotection, free amine

To a solution of the N-Boc protected compound (1.0 equiv.) in CH<2>Ch (0.04 M) at 0 °C was slowly added TFA (35.0 equiv.) (CH<2>Ch/TFA 10/1). The mixture was allowed to come to room temperature and stirred until completion (TLC monitoring). The solvent was then removed under reduced pressure. The residue was suspended in CH<2>Cl<2>and 2 M aqueous NaOH solution was added. The mixture was stirred for 30 min and extracted with CH<2>Ch. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to afford the desired product.

General procedure F2: Boc deprotection (TFA amine salt)

To a solution of the N-Boc protected compound (1.0 equiv.) in CH<2>Cl<2>(0.04 M) at 0 °C was slowly added TFA (35.0 equiv.). The mixture was allowed to warm to room temperature and stirred until completion (TLC monitoring). The solvent was then removed under reduced pressure and the residue coevaporated 3 times with EfeO. The resulting solid was suspended in Et<2>O, filtered, washed with EfeO and pentane, and dried at 60 °C in vacuo to afford the desired amine as a TFA salt.

General procedure G: Synthesis of urea using isocyanates

To a solution of the desired amine (1.0 equiv.) in anhydrous CH<2>Cl<2>(0.07 M) under argon was added DIPEA (3.0 equiv.). The solution was cooled to 0 °C and the corresponding isocyanate (1.1 equiv.) was added. The mixture was stirred at this temperature until completion (TLC monitoring). The solvent was then removed under reduced pressure and the residue was purified by silica gel column chromatography to afford the desired product.

General procedure H: Synthesis of urea using 4-nitrophenyl chloroformate

To a solution of the desired aniline (1.0 equiv.) in THF (0.07 M) at 0 °C was added DIPEA (1.1 to 2.1 equiv.) and 4-nitrophenyl chloroformate (1.2 equiv.). The mixture was stirred at 0 °C until complete disappearance of the starting material (TLC monitoring). Then, the second amine (free or as a salt derivative) (1.2 equiv.) and DIPEA (2.1 equiv.) were added and the reaction mixture was stirred at 50 °C until completion (TLC monitoring). The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to afford the desired product.

General procedure I: Synthesis of urea by Curtius rearrangement

To a solution of acid (1.0 equiv.) was added Et<3>N (1.2 equiv.) in THF (0.05 M) at 0 °C. Ethyl chloroformate (1.5 equiv.) was added and the reaction was stirred for 1 h at 0 °C (TLC monitoring). Then, a solution of NaN<3>(1.5 equiv.) in H<2>O was added at 0 °C and stirred for 1.5 h (TLC monitoring). The reaction was quenched with ice and quickly extracted with EtOAc, dried over MgSO<4>, filtered and the solvent was removed under reduced pressure without heating. The acyl azide was dissolved in toluene (0.05 M) and stirred for 1 h at reflux. The toluene was removed under reduced pressure. To this freshly prepared isocyanate was added a solution of amine (1.0 equiv.) and DIPEA (2.2 equiv.) in anhydrous CH<2>Cb at 0 °C. The mixture was stirred at this temperature until completion (TLC monitoring). The solvent was then removed under reduced pressure and the residue was purified by silica gel column chromatography to provide the desired product.

General procedure J: Boc deprotection (HCl amine salt)

Hydrochloric acid (4 M HCl solution in dioxane, 18 equiv.) was slowly added to a solution of the N-Boc protected compound (1.0 equiv.) in dioxane (0.11 M) at 0 °C. The mixture was allowed to warm to room temperature and stirred until completion (TLC monitoring). Diethyl ether was added to precipitate the amine salt which was filtered and washed with Ephedrine and then dried at 60 °C in vacuo to afford the desired amine as a HCl salt.

General procedure K: Modified Fisher synthesis

A suspension of hydrazone (1.0 equiv.) in diphenyl ether (0.22 M) was degassed for 20 min with Ar and then refluxed for 3 h. After cooling to room temperature, the solid was filtered, washed several times with Et<2>O and then dried at 60 °C in vacuo to provide the desired product.

General procedure L: Mitsunobu reaction

To a solution of 3-nitrophenol (1.0 equiv.) in dry THF (0.28 M) under argon were added the primary alcohol (2.0 equiv.) and triphenylphosphine (1.7 equiv.). The mixture was stirred at room temperature for 10 min until complete dissolution of triphenylphosphine. Then, diisopropyl azodicarboxylate (DIAD) (1.7 equiv.) was added dropwise at room temperature over 5 to 10 min. The reaction mixture was stirred at room temperature for 24 h, then diluted with H<2>O and extracted twice with Et<2>O. The combined organic layers were dried over MgSO<4>, filtered, and concentrated under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography to afford the desired product.

General procedure M: Williamson reaction

To a solution of 3-nitrophenol (1.0 equiv.) in dry MeCN (0.80 M) under argon was added K<2>CO<3>(1.6 equiv.) and the corresponding alkyl halide (8.0 equiv.). The resulting suspension was stirred at reflux until complete conversion (TLC monitoring), then concentrated under reduced pressure. The residue was partitioned between DCM and H<2>O. The aqueous phase was separated and extracted twice with DCM, then the combined organic phases were dried over MgSO<4>, filtered, and concentrated under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography to afford the desired product.

General procedure N: Reduction of the nitro group

A 50 mL round bottom flask was charged with the aromatic nitro compound (1.0 equiv.) and then a 10 wt % Pd/C suspension (0.1 equiv.) in MeOH (0.18 M) was added. The flask was flushed with hydrogen and stirred at room temperature under hydrogen gas until complete conversion of the starting material. The reaction mixture was then filtered through Celite, washed with methanol and concentrated under reduced pressure to provide the desired amine.

General procedure O:N-alkylation

To a solution of alkyl halide (1.0 equiv.) in dry THF (0.18 M) under argon was added the amine (3.1 equiv.). The reaction mixture was stirred at reflux until complete conversion, then cooled to room temperature and concentrated under reduced pressure. The residue was stirred in 1 M HCl aqueous solution for 15 min, washed twice with Et<2>O, then treated with 10% NaOH aqueous solution to pH -10-13. The aqueous layer was extracted with Et<2>O (three times), then the combined organic layers were dried over MgSO<4>, filtered, and concentrated under reduced pressure to afford the desired product.

General procedure P: Ullmann coupling with Ar-I

An oven-dried microwave reaction vial was charged with a magnetic stir bar, 3-aminophenol (1.2 equiv.), copper(I) iodide (5 mol%), 2-picolinic acid (10 mol%), aryl iodide (1.0 equiv.), and K<3>PO<4>(2.0 equiv.). The tube was then evacuated and filled with argon. The evacuation/filling sequence was repeated two additional times. Under argon, the remaining liquid reagents were added, followed by dry DMSO (0.5 M). The vial was sealed and then placed on a hot plate preheated to 80 °C and the reaction mixture was stirred vigorously for 18-36 h. The reaction mixture was cooled to room temperature. EtOAc and H<2>O were added, the aqueous layer was separated and extracted with EtOAc (2x). The combined organic layers were washed with brine (3x), dried over MgSO<4>, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to provide the desired aniline.

Family 1.

3-methyl pyrolopyrimidine derivatives

5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ol (1)

To a solution of LiOH (3.5 g, 147.7 mmol, 1.5 equiv.) in anhydrous MeOH (120 mL) was added cyanoacetamide (12.4 g, 147.7 mmol, 1.5 equiv.) under argon. This solution was stirred for 20 min and the addition of a solution of phthalimidoacetone in anhydrous THF (140 mL) was performed over 30 min. The reaction mixture was then stirred 2 h at room temperature and 1 h at 55 °C. A solution of sodium methoxide (NaOMe) (25% in methanol, 31.6 mL, 147.7 mmol, 1.5 equiv.) was added dropwise and the mixture was stirred for 3 h. Ethyl formate (HCOOEt, 39.7 mL, 492.2 mmol, 5.0 equiv.) was then added followed by a solution of NaOMe (25% in methanol, 63.2 mL, 295.3 mmol, 3.0 equiv.) and the reaction mixture was stirred at 55 °C overnight. After cooling, the reaction mixture was diluted with water (500 mL), heated at 60 °C for 1 h, and then concentrated under reduced pressure to a small volume (<500 mL). The resulting solution was slowly acidified to pH = 7 with 6 N aqueous HCl solution, cooled to about 5 °C, and stirred at this temperature for 30 min. The solid was filtered, washed with water (100 mL) and dried at 50 °C in vacuo overnight to afford compound 1 (8.65 g, 59%) as a light brown solid.<1>H NMR (250 MHz, DMSO-d6) 511.50 (brs, 2H, 2 x NH), 7.73 (s, 1H, CH), 6.75-6.72 (m, 1H, CH), 2.26 (d, J = 1.1 Hz, 3H, CH<3>). Org. Process Res. Dev. 2007, 11 (1), 86-89.

4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (2)

The hydroxylated compound 1 (2.0 g, 13.4 mmol) was dissolved in POC (50 mL) and stirred under reflux for 1.5 h. After cooling, the mixture was slowly poured into a vigorously stirring ice-water bath and stirred for 30 min. The mixture was carefully neutralized to pH 7 with solid NaOH. The mixture was then extracted with CH Cl (3 x 150 mL). The combined organic layers were dried over MgSO , filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel using a gradient solvent system of PE/EtOAc from 100/0 to 70/30. Finally, the product was precipitated from acetone/PE mixture to give 2 (3.6 g, 81%) as a beige solid.<1>H NMR (250 MHz, CDC<b>) 59.49 (brs, 1H, NH), 8.60 (s, 1H, CH), 7.11 (dd, J = 2.3 Hz, J = 1.2 Hz, 1H, CH), 2.50 (d, J = 1.2 Hz, 3H, CH<3>). West, R. A. J. Org. Chem. 1961, 26, 4959-4961.

Tert-Butyl 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridin-1(2H)-carboxate (3)

The reaction was carried out as described in General Procedure D using chlorinated dichloride 2 (0.50 g, 2.99 mmol), N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (1.02 g, 3.29 mmol, 1.1 equiv.), Pd(PPh<3>)<4>(0.35 g, 0.30 mmol, 0.1 equiv.) in THF (12 mL) and 2 M Na<2>CO<3> solution (4.5 mL, 8.98 mmol, 3.0 equiv.). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH<2>C<h>/acetone from 90/10 to 60/40 to provide compound 3 (0.63 g, 67%) as a beige solid. Rf(CH<2>C<h>/acetone 60/40) 0.33. Mp: 190 - 192 °C.<1>H NMR (250 MHz, CDC<b>) 810.40 (brs, 1H, NH), 8.81 (s, 1H, CH), 7.12 (s, 1H, CH), 6.06 - 5.87 (m, 1H, CH), 4.24 - 4.09 (m, 2H, CH<2>), 3.72 (t, J = 5.6 Hz, 2H, CH<2>), 2.77 - 2.65 (m, 2H, CH<2>), 2.29 (d, J = 1.1 Hz, 3H, CH<3>), 1.51 (s, 9H, 3 x CH<3>). HRMS (EI-MS) m/z calcd. for C<17>H<23>N<4>O<2>[M+H]<+>: 315.1816, found: 315.1814.

5-Methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine hydrochloride (4)

To a solution of the N-Boc protected compound 3 (1.68 g, 5.35 mmol) in 1,4-dioxane (5 mL) at 0 °C was added a 4 M solution of HCl in 1,4-dioxane (20 mL, 80.0 mmol, 15.0 equiv.). The reaction mixture was stirred for 1 h at room temperature. Upon completion, Et<2>O (200 mL) was added and the resulting precipitate was filtered and washed with Et<2>O (3 x 30 mL) to afford compound 4 (1.47 g, 96%) as a beige solid. Mp: > 260 °C.<1>H NMR (400 MHz, DMSO-de) 813.23 (brs, 1H, NH), 9.94 (brs, 2H, NH H<+>), 8.98 (s, 1H, CH), 7.73 (s, 1H, CH), 6.39 - 6.28 (m, 1H, CH), 4.48 - 4.11 (m, 1H, H<+>), 3.91 - 3.81 (m, 2H, CH<2>), 3.41 - 3.30 (m, 2H, CH<2>), 2.98 - 2.88 (m, 2H, CH<2>), 2.31 (d, J = 1.2 Hz, 3H, CH<3>). HRMS (EI-MS) m/z calcd. for C<12>H<15>N<4>[M+H]<+>: 215.1291, found: 215.1295.

Subfamily 1.1.

3-Methylpyrrolopyrimidine derivatives with an unsubstituted hydropyridine

4 5-24, 26, 28-31

Example 1: 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-M)-N-phenyl-3,6-dihydropyridine-1 (2H)-carboxamide (5)

The reaction was carried out as described in the general procedure by using the amine 4 (70 mg, 0.24 mmol) in anhydrous CH < 2 > Cl < 2 > (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH < 2 > C < h >/acetone from 100/0 to 40/60 to provide compound 5 (64 mg, 80%) as an off-white solid. R f (CH < 2 > Cl < 2 >/acetone 30/70) 0.35. Mp: 245 - 247 °C.<1>H NMR (250 MHz, MeOD-d<4>) 88.63 (s, 1H, CH), 7.45 - 7.36 (m, 2H, 2 x CH), 7.33 - 7.24 (m, 2H, 2 x CH), 7.23 (d, J = 1.3 Hz, 1H, CH), 7.09 - 6.98 (m, 1H, CH), 6.08 - 6.00 (m, 1H, CH), 4.29 (q, J = 2.8 Hz, 2H, CH<2>), 3.84 (t, J = 5.6 Hz, 2H, CH<2>), 2.80 - 2.68 (m, 2H, CH<2>), 2.30 (d, J = 1.2 Hz, 3H, CH<3>). HRMS (EI-MS) m/z calcd. for C<19>H<20>N<5>O[M+H]<+>: 334.1662, found: 334.1661.

Example 2: W-(3-fluorophenyl)-4-(5-methyl-7H-pyrrolo[2,3-d]pmmidin-4-yl)-3,6-dihydropindine-1(2H)-carboxamide (6)

The reaction was carried out as described in the general procedure by using the amine 4 (70 mg, 0.24 mmol) in anhydrous CH<2>Cl<2> (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH<2>C<h>/acetone from 90/10 to 60/40 to provide compound 65 (51 mg, 60%) as an off-white solid. Rf (CH<2>C<h>/acetone 70/30) 0.28. Mp: 241 -243 °C.<1>H NMR (400 MHz, DMSO-de) 811.83 (brs, 1H, NH), 8.79 (brs, 1H, NH), 8.65 (s, 1H, CH), 7.49 (d, J = 12.4 Hz, 1H, CH), 7.38 - 7.23 (m, 3H, 3 x CH), 6.86 - 6.66 (m, 1H, CH), 6.05 (s, 1H, CH), 4.34 - 4.10 (m, 2H, CH<2>), 3.81 - 3.69 (m, 2H, CH2), 2.74 - 2.64 (m, 2H, CH2), 2.23 (s, 3H, CH3). 19F NMR (376 MHz, DMSO-d6) 8 -112.7 - -113.0 (m). HRMS (EI-MS) m/z calcd. for C19H19FN5O [M+H]+: 352.1568, found: 352.1570.

Example 3: W-(3-chlorophen¡l)-4-(5-met¡l-7H-pyrrolo[2,3-d]pyr¡m¡din-4-¡l)- 3,6-d¡hydro¡r¡dina-1(2H)-carboxamide (7)

The reaction was carried out as described in the general procedure by using amine 4 (70 mg, 0.24 mmol) in anhydrous CH 2 Cl 2 (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch 2 /acetone from 90/10 to 60/40 to give compound 7 (42 mg, 47%) as an off-white solid. Rf (CH 2 Cl 2 /acetone 70/30) 0.29. Mp: 232 - 234 °C. 1H NMR (400 MHz, DMSO-d6) 8 11.84 (brs, 1H, NH), 8.77 (brs, 1H, NH), 8.65 (s, 1H, CH), 7.70 (t, J = 2.1 Hz, 1H, CH), 7.45 (dd, J = 8.2 Hz, J = 2.0 Hz, 1H, CH), 7.32 (s, 1H, CH), 7.27 (t, J = 8.1 Hz, 1H, CH), 6.99 (dd, J = 8.0 Hz, J = 2.1 Hz, 1H, CH), 6.09 - 6.01 (m, 1H, CH), 4.26 - 4.19 (m, 2H, CH2), 3.74 (t, J = 5.6Hz, 2H, CH2), 2.73 - 2.61 (m, 2H, CH2), 2.24 (s, 3H, CH3). HRMS (EI-MS) m/z calcd. for C19H19CIN5O [M+H]+: 368.1273, found: 368.1275.

Example 4: W-(3-bromophen¡l)-4-(5-met¡l-7H-pyrrolo[2,3-d]pyr¡m¡din-4-¡l)- 3,6-d¡hydro¡r¡dina-1(2H)-carboxamide (8)

The reaction was carried out as described in the general procedure by using amine 4 (70 mg, 0.24 mmol) in anhydrous CH 2 Cl 2 (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch 2 /acetone from 90/10 to 60/40 to give compound 8 (69 mg, 70%) as a white solid. Rf (CH 2 Ch 2 /acetone 70/30) 0.28. Mp: 223 - 225 °C. 1H NMR (400 MHz, DMSO-d6) 811.82 (brs, 1H, NH), 8.75 (brs, 1H, NH), 8.65 (s, 1H, CH), 7.83 (s, 1H, CH), 7.50 (d, J = 8.3 Hz, 1H, CH), 7.31 (s, 1H, CH), 7.21 (t, J = 8.0 Hz, 1H, CH), 7.12 (d, J = 8.0 Hz, 1H, CH), 6.05 (s, 1H, 4.30 - 4.13 (m, 2H, CH2), 3.73 (t, J = 5.6 Hz, 2H, CH2), 2.75 - 2.62 (m, 2H, CH2), 2.23 (s, 3H, CH3). HRMS (EI-MS) m/z calcd. for C19H19BrN5O [M+H]+: 412.0767, found: 412.0766.

Example 5: N-(3-methoxy¡phen¡l)-4-(5-methyl¡l-7H-pyrrolo[2,3-d]pyr¡m¡din-4-¡l )-3,6-di¡hydro¡r¡dina-1(2H)-carboxamide (9)

The reaction was carried out as described in the general procedure by using amine 4 (70 mg, 0.24 mmol) in anhydrous CH 2 Cl 2 (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch 2 /acetone from 90/10 to 60/40 to give compound 9 (40 mg, 46%) as a white solid. Rf (CH 2 Ch 2 /acetone 70/30) 0.30. Mp: 212 - 214 °C. 1H NMR (400 MHz, DMSO-de) 811.82 (brs, 1H, NH), 8.65 (s, 1H, CH), 8.56 (brs, 1H, NH), 7.38 - 7.06 (m, 4H, 4 x CH), 6.67 -6.37 (m, 1H, CH), 6.15 - 5.95 (m, 1H, CH), 4.22 (s, 2H, CH2), 3.72 (m, 5H, CH2 OCH3), 2.74 - 2.59 (m, 2H, CH2), 2.24 (s, 3H, CH3). HRMS (EI-MS) m/z calcd. for C20H22N5O2 [M+H]+: 364.1768, found: 364.1770.

Example 6: N-(3-cyanophen¡l)-4-(5-met¡l-7H-pyrrolo[2,3-d]pyr¡m¡d¡n-4-¡l )-3,6-di¡hydro¡r¡dina-1(2H)-carboxamide (10)

The reaction was carried out as described in the general procedure by using amine 4 (70 mg, 0.24 mmol) in anhydrous CH 2 Cl 2 (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Cl 2 /acetone from 90/10 to 40/60 to give compound 10 (65 mg, 76%) as an off-white solid. Rf (CH 2 Ch /acetone 50/50) 0.19. Mp: 207 - 209 °C. 1H NMR (250 MHz, DMSO-de) 88.63 (s, 1H, CH), 7.89 - 7.86 (m, 1H, CH), 7.71 (ddd, J = 8.2 Hz, J = 2.3 Hz, J = 1.2 Hz, 1H, CH), 7.44 (td, J = 7.6 Hz, J = 2.4 Hz, 1H, CH), 7.35 (dt, J = 7.7 Hz, J = 1.4 Hz, 1H, CH), 7.24 (d, J = 1.2 Hz, 1H, CH), 6.13 - 5.98 (m, 1H, CH), 4.37 - 4.23 (m, 2H, CH2), 3.86 (t, J = 5.6 Hz, 2H, CH2), 2.80 - 2.67 (m, 2H, CH2), 2.31 (d, J = 1.2 Hz, 3H, CH3). 1HRMS (EI-MS) m/z calcd. for C20H19N6O [M+H]+: 359.1615, found: 359.1616.

Example 7: 4-(5-met¡l-7H-pyrrolo[2,3-d]p¡r¡m¡din-4-¡l)-N-(3-(trifluoromet¡ l)phen¡l)-3,6-di¡hydro¡r¡d¡n-1(2H)-carboxamide (11)

The reaction was carried out as described in the general procedure by using amine 4 (70 mg, 0.24 mmol) in anhydrous CH 2 Cl 2 (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch 2 /acetone from 80/20 to 30/70 to give compound 11 (69 mg, 72%) as an off-white solid. R f (CH 2 Ch 2 /acetone 50/50) 0.33. Mp: degradation 231 °C. 1H NMR (400 MHz, DMSO-d6) 8 11.83 (brs, 1H, NH), 8.93 (brs, 1H, NH), 8.65 (s, 1H, CH), 7.97 (s, 1H, CH), 7.80 (d, J = 8.3 Hz, 1H, CH), 7.48 (t, J = 8.0 Hz, 1H, CH), 7.32 (s, 1H, CH), 7.28 (d, J = 7.8 Hz, 1H, CH), 6.11 - 5.96 (m, 1H, CH), 4.30 - 4.11 (m, 2H, CH2), 3.76 (t, J = 5.6 Hz, 2H, CH2), 2.73 - 2.61 (m, 2H, CH2), 2.24 (s, 3H, CH3). 19F NMR (376 MHz, DMSO-d6) 8 -61.2 (s). HRMS (EI-MS) m/z calcd. for C20H19F3N5O [M+H]+: 402.1536, found: 402.1536.

Example_______ 8: N-(4-chloro-3-(trifluoromethyl)phenyl)-4-(5-methyl-7H-pyrrolo[2,3-d]pyrm ¡d¡n-4-¡l)-3,6-d¡hydro¡r¡d¡na-1(2H)-carboxamide (12)

The reaction was carried out as described in the general procedure by using amine 4 (70 mg, 0.24 mmol) in anhydrous CH 2 Cl 2 (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch 2 /acetone from 80/20 to 40/60 to give compound 12 (49 mg, 47%) as an off-white solid. Rf (CH 2 Ch 2 /acetone 60/40) 0.22. Mp: 228 - 230 °C. 1H NMR (400 MHz, DMSO-de) 811.83 (brs, 1H, NH), 9.03 (brs, 1H, NH), 8.65 (s, 1H, CH), 8.10 (d, J = 2.6 Hz, 1H, CH), 7.85 (dd,J = 8.8Hz,J =2.6Hz, 1H, CH), 7.59 (d,J = 8.8Hz, 1H, CH), 7.31 (s, 1H, CH), 6.10 - 6.02 (m, 1H, CH), 4.29 - 4.18 (m, 2H, CH2), 3.75 (t, J = 5.6 Hz, 2H, CH2), 2.73 - 2.64 (m, 2H, CH2), 2.23 (s, 3H, CH3). 19F NMR (376 MHz, DMSO-d6) 8 -61.4 (s). HRMS (EI-MS) m/z calcd. for C20H18CIF3N5O [M+H]+: 436.1146, found: 436.1145.

Example 9: 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(naphthalen-2-yl)-3,6-dihydropyridine-1(2H)-carboxamide ( 13)

The reaction was carried out as described in the general procedure by using the amine 4 (70 mg, 0.24 mmol) in anhydrous CH 2 Cl 2 (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch / acetone from 80/20 to 30/70 to provide compound 13 (55 mg, 60%) as an off-white solid. Rf (CH 2 Ch / acetone 50/50) 0.31. Mp: 233 - 235 °C. 1H NMR (250 MHz, MeOD-d4) 88.64 (s, 1H, CH), 7.91 (d, J = 2.1 Hz, 1H, CH), 7.84 - 7.69 (m, 3H, 3xCH), 7.56 (dd, J = 8.8 Hz, J = 2.2 Hz, 1H, CH), 7.47 - 7.30 (m, 2H, 2 x CH), 7.24 (d, J = 1.2 Hz, 1H, CH), 6.13 - 5.99 (m, 1H, CH), 4.39 - 4.31 (m, 2H, CH2), 3.90 (t, J = 5.6 Hz, 2H, CH2), 2.83 - 2.69 (m, 2H, CH2), 2.33 (d, J = 1.2 Hz, 3H, CH3). HRMS (EI-MS) m/z calcd. for C23H22N5 O[M+H]+: 384.1819, found: 384.1815.

Example___________10: W-(benzo[d][1,3]dioxol-5-yl)-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine -1(2H)-carboxamide (14)

The reaction was carried out as described in the general procedure by using the amine 4 (70 mg, 0.24 mmol) in anhydrous CH 2 Cl 2 (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch / acetone from 80/20 to 40/60 to provide compound 14 (32 mg, 35%) as an off-white solid. Rf (CH 2 Ch / acetone 60/40) 0.13. Mp: 235 - 237 °C. 1H NMR (400 MHz, DMSO-de) 811.85 (brs, 1H, NH), 8.64 (s, 1H, CH), 8.47 (brs, 1H, NH), 7.38 - 7.24 (m, 1H, CH), 7.22 - 7.11 (m, 1H, CH), 6.93 - 6.69 (m, 2H, 2 x CH), 6.09 - 5.81 (m, 3H, CH OCH2O), 4.28 - 4.05 (m, 2H, CH2), 3.79 - 3.59 (m, 2H, CH2), 2.73 - 2.58 (m, 2H, CH2), 2.23 (d, J = 17.4 Hz, 3H, CH3). HRMS (EI-MS) m/z calcd. for C20H20N5O3 [M+H]+: 378.1561, found: 378.1560.

Example 11: 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(3-phenoxyphenyl)-3,6-dihydropyridin-1 (2H)-carboxamide (15)

The reaction was carried out as described in the general procedure by using the amine 4 (70 mg, 0.24 mmol) in anhydrous CH 2 Cl 2 (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch / acetone from 80/20 to 70/30 to provide compound 15 (50 mg, 49%) as a white solid. Rf (CH 2 Ch / acetone 60/40) 0.21. Mp: 196 - 198 °C. 1H NMR (400 MHz, MeOD-d4) 88.62 (s, 1H, CH), 7.41 - 6.93 (m, 9H, 9xCH), 6.69 - 6.61 (m, 1H, CH), 6.13 - 5.96 (m, 1H, CH), 4.30 - 4.22 (m, 2H, CH2), 3.82 (t, J = 5.6 Hz, 2H, CH2), 2.77 - 2.64 (m, 2H, CH2), 2.29 (s, 3H, CH3). HRMS (EI-MS) m/z calcd. for C25H24N5O2 [M+H]+: 426.1925, found: 426.1923.

Example 12: 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(4-phenoxyphenyl)-3,6-dihydropyridin-1(2H)-carboxamide (16)

The reaction was carried out as described in the general procedure by using the amine 4 (70 mg, 0.24 mmol) in anhydrous CH 2 Cl 2 (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch / acetone from 80/20 to 30/70 to provide compound 16 (87 mg, 85%) as a white solid. Rf (CH 2 Ch / acetone 60/40) 0.18. Mp: 224 - 226 °C. 1H NMR (400 MHz, DMSO-d6) 8 11.83 (brs, 1H, NH), 8.65 (s, 1H, CH), 8.61 (brs, 1H, NH), 7.52 (d, J = 8.9 Hz, 2H, 2 x CH), 7.35 (t, J = 7.8 Hz, 2H, 2 x CH), 7.32 (s, 1H, CH), 7.08 (t, J = 7.4 Hz, 1H, CH), 6.95 (d, J = 8.3 Hz, 4H, 4xCH), 6.05 (s, 1H, CH), 4.28 - 4.17 (m, 2H, CH2), 3.74 (t, J = 5.6 Hz, 2H, CH2), 2.75 - 2.62 (m, 2H, CH2), 2.24 (s, 3H, CH3). HRMS (EI-MS) m/z calcd. for C25H24N5O2 [M+H]+: 426.1925, found: 426.1927.

Example 13: N-([1,1'-biphenyl]-3-yl)-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine- 1(2H)-carboxamide (17)

The reaction was carried out as described in the general procedureIusing biphenyl-3-carboxylic acid (61 mg, 0.31 mmol) and the amine4(89 mg, 0.31 mmol). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Ch/acetone from 100/0 to 60/40 to afford compound17(43 mg, 34%) as a white solid. Rf (CH2Ch/acetone 70/30) 0.31. Mp: 235 -237 °C. 1H NMR (400 MHz, DMSO-de) 8 11.83 (brs, 1H, NH), 8.68 (brs, 1H, NH), 8.65 (s, 1H, CH), 7.83 (s, 1H, CH), 7.71 - 7.18 (m, 9H, 9xCH), 6.17 - 5.97 (m, 1H, CH), 4.33 - 4.15 (m, 2H, CH2), 3.83 - 3.67 (m, 2H, CH2), 2.78 - 2.62 (m, 2H, CH2), 2.25 (s, 3H, CH3). HRMS (EI-MS) m/z calcd. for C25H24N5 O[M+H]+: 410.1975, found: 410.1983.

Example 14: 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(3-(pyridin-4-yl)phenyl)-3,6-dihydropyridin-1( 2H)-carboxamide (18)

The reaction was carried out as described in the general procedureIusing 3-(pyridin-4-yl)benzoic acid (62 mg, 0.31 mmol) and the amine4(89 mg, 0.31 mmol). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Cl2/acetone from 100/0 to 50/50 to provide compound18(19 mg, 15%) as a beige solid. Rf (CH2Ch/acetone 50/50) 0.24. Mp: 208 - 210 °C. 1H NMR (400 MHz, DMSO-de) 8 11.83 (brs, 1H, NH), 8.77 (brs, 1H, NH), 8.71 - 8.59 (m, 3H, 3 x CH), 8.01 - 7.90 (m, 1H, CH), 7.73 - 7.56 (m, 2H, 2 x CH), 7.45 - 7.36 (m, 3H, 3xCH), 7.32 (s, 1H, CH), 6.07 (s, 1H, CH), 4.26 (s, 2H, CH2), 3.77 (s, 2H, CH2), 2.70 (s, 2H, CH2), 2.25 (s, 3H, CH3). HRMS (EI-MS) m/z calcd. for C24H24N6 O[M+H]+: 411.1928, found: 411.1933.

Example 15: W-(3-(1H-pyrrol-1-¡l)phen¡l)-4-(5-met¡l-7H-pyrrolo[2,3-d]p¡r¡ m¡d¡n-4-¡l)-3,6-di¡hydro¡r¡d¡na-1(2H)-carboxamide (19)

The reaction was carried out as described in the general procedure using 3-(1H-pyrrole-1-yl)benzoic acid (58 mg, 0.31 mmol) and amine (89 mg, 0.31 mmol, 1.0 equiv.). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Cl2/acetone from 100/0 to 50/50 to provide compound 19 (61 mg, 49%) as an off-white solid. Rf (CH2Cl2/acetone 50/50) 0.28. Mp: 215 - 217 °C1H NMR (400 MHz, DMSO-de) 8 11.85 (brs, 1H, NH), 8.75 (brs, 1H, NH), 8.66 (s, 1H, CH), 7.76 (s, 1H, CH), 7.52 - 7.06 (m, 6H, 6 x CH), 6.26 (s, 2H, 2 x CH), 6.18 - 5.97 (m, 1H, CH), 4.37 - 4.09 (m, 2H, CH2), 3.85 - 3.69 (m, 2H, CH2), 2.77 - 2.63 (m, 2H, CH2), 2.24 (s, 3H, CH3). HRMS (EI-MS) m/z calcd. for C23H23N6 O[M+H]+: 399.1928, found: 399.1928.

Example 16: W-(3-ethylphen¡l)-4-(5-met¡l-7H-pyrrolo[2,3-d]p¡r¡m¡d¡n-4-¡l )-3,6-di¡hydro¡r¡dina-1(2H)-carboxamide (20)

The reaction was carried out as described in the general procedure using 3-ethylenyl (31 mL, 0.25 mmol) and amine (85 mg, 0.30 mmol) in THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH (Ch)/acetone from 80/20 to 30/70 to give compound (52 mg, 58%) as a white solid. Rf (CH (Ch)/acetone 60/40) 0.20. Mp: 210 -212 °C. 1H NMR (400 MHz, DMSO-de) 811.82 (brs, 1H, NH), 8.65 (s, 1H, CH), 8.51 (brs, 1H, NH), 7.40 - 7.28 (m, 3H, 3 x CH), 7.14 (t, J = 7.7 Hz, 1H, CH), 6.80 (d, J = 7.6 Hz, 1H, CH), 6.04 (s, 1H, CH), 4.30 - 4.14 (m, 2H, CH2), 3.73 (t, J = 5.6 Hz, 2H, CH2), 2.73 - 2.64 (m, 2H, CH2), 2.55 (q, J = 7.7 Hz, 2H, CH2), 2.24 (s, 3H, CH3), 1.17 (t, J = 7.6 Hz, 3H, CH3). HRMS (EI-MS) m/z calcd. for C21H24N5 O[M+H]+: 362.1975, found: 362.1975.

Example 17: 4-(5-met¡l-7H-pyrrolo[2,3-d]p¡r¡m¡din-4-¡l)-N-(3-(trifluoromethox¡ )phen¡l)-3,6-di¡hydro¡r¡d¡n-1(2H)-carboxamide (21)

The reaction was carried out as described in the general procedure using 3-(trifluoromethoxy)aniline (33 mL, 0.25 mmol) and amine (85 mg, 0.30 mmol, 1.2 equiv.) in THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CHCh/acetone from 80/20 to 20/80 to give compound (73 mg, 70%) as a white solid. Rf (CHCh/acetone 60/40) 0.18. Mp: 227 - 229 °C. 1H NMR (400 MHz, DMSO-de) 8 11.83 (brs, 1H, NH), 8.87 (brs, 1H, NH), 8.65 (s, 1H, CH), 7.67 (s, 1H, CH), 7.52 (d, J = 8.3 Hz, 1H, CH), 7.36 (t, J = 8.3 Hz, 1H, CH), 7.32 (s, 1H, CH), 6.91 (d, J = 8.2 Hz, 1H, CH), 6.05 (s, 1H, CH), 4.33 - 4.13 (m, 2H, CH2), 3.75 (t, J = 5.7 Hz, 2H, CH2), 2.76 - 2.61 (m, 2H, CH2), 2.23 (s, 3H, CH3). 19F NMR (376 MHz, DMSO-d6) 8 -56.6 (s). HRMS (EI-MS) m/z calcd. for C20H19F3N5O [M+H]+: 418.1485, found: 418.1484.

Example 18: 3-(4-(5-met¡l-7H-pyrrolo[2,3-d]p¡r¡m¡din-4-¡l)-1,2,3,6 phenyl-tetrah¡drop¡r¡din-1-carboxam¡do)dimet¡lcarbamate (22)

The reaction was carried out as described in the general procedure using 3-aminophenylmethyl carbamate (45 mg, 0.25 mmol) and amino4 (85 mg, 0.30 mmol, 1.2 equiv.) in THF (4 mL). The crude mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Ch/acetone from 90/10 to 20/80 to provide compound22 (60 mg, 57%) as a white solid. Rf (CH2Ch/acetone 60/40) 0.21. Mp: 214 - 216 °C. 1H NMR (400 MHz, DMSO-de) 811.81 (brs, 1H, NH), 8.89 - 8.45 (m, 2H, NH CH), 7.60 - 7.10 (m, 4H, 4 x CH), 6.87 - 6.49 (m, 1H, CH), 6.07 - 5.92 (m, 1H, CH), 4.29 - 4.09 (m, 2H, CH2), 3.71 (t, J = 5.7 Hz, 2H, CH2), 3.03 (s, 3H, NCH3), 2.91 (s, 3H, NCH3), 2.75 - 2.60 (m, 2H, CH2), 2.23 (s, 3H, CH3). HRMS (EI-MS) m/z calcd. for C22H25N6O3 [M+H]+: 421.1983, found: 421.1978.

3-(1H-¡m¡dazol-1-¡l)an¡line (23)

An oven-dried microwave vial was charged with a magnetic stir rod, CuL (28 mg, 0.15 mmol, 0.05 equiv.), KPO (1.31 g, 6.17 mmol, 2.1 equiv.), amdazole (0.20 g, 2.94 mmol, 1.0 equiv.), and 1,10-phenanthrolline (52 mg, 0.29 mmol, 0.1 equiv.). The tube was then evacuated and filled with argon. The evacuation/filling sequence was repeated two additional times. Under a counterflow of argon, 3-iodoaniline (0.42 mL, 3.53 mmol, 1.2 equiv.) and degassed 1,4-doxane (1.5 mL) were added via syringe. The tube was placed in a preheated oil bath at 110 °C, and the solution was stirred vigorously for 24 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (2-3 mL), filtered through a plug of Celite, and rinsed with EtOAc. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica gel using a gradient solvent system of PE/EtoAc from 90/10 to 80/20 to provide compound 23 (0.38 g, 82%) as a beige solid. 1H NMR (250 MHz, DMSO-de) 87.82 (s, 1H, CH), 7.28 - 7.16 (m, 3H, 3 x CH), 6.79 - 6.73 (m, 1H, CH), 6.70 - 6.63 (m, 2H, 2 x CH), 3.75 (brs, 2H, NH2). All spectral data were in accordance with literature values as found in Suresh, P.; Pitchuman, K. J. Org. Chem. 2008, 73, 9121-9124.

Example__________ 19: W-(3-(1H-¡m¡dazol-1-¡l)phen¡l)-4-(5-methyl-7H-pyrrolo[2,3-d]p¡r ¡m¡d¡n-4-¡l)-3,6-d¡hydro¡r¡d¡na-1(2H)-carboxamide (24)

The reaction was carried out as described in the general procedure using aniline 23 (40 mg, 0.25 mmol) and amine 4 (85 mg, 0.30 mmol, 1.2 equiv.) in THF (4 mL). The crude mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch / acetone from 90/10 to 40/60 to provide compound 24 (45 mg, 45%) as an off-white solid. Rf (CH 2 Ch / acetone 50/50) 0.23. Mp: 245 - 247 °C1H NMR (400 MHz, DMSO-de) 8 11.84 (brs, 1H, NH), 8.83 (brs, 1H, NH), 8.65 (s, 1H, CH), 8.13 (s, 1H, H), 7.80 (t, J = 2.2 Hz, 1H, CH), 7.62 (s, 1H, CH), 7.52 (dd, J = 8.0 Hz, J = 2.0 Hz, 1H, CH), 7.39 (t, J = 8.1 Hz, 1H, CH), 7.32 (s, 1H, CH), 7.20 (dd, J = 7.9 Hz, J = 2.2 Hz, 1H, CH), 7.11 (s, 1H, CH), 6.11 - 6.02 (m, 1H, CH), 4.32 - 4.16 (m, 2H, CH2), 3.76 (t, J = 5.5 Hz, 2H, CH2), 2.70 (s, 2H, CH2), 2.24 (s, 3H, CH3). HRMS (EI-MS) m/z calcd. for C22H22N7 O[M+H]+: 400.1880, found: 400.1880.

3-(1H-1,2,4-triazol-1-yl)aníline(84) 25 GB 156

An oven-dried microwave vial was charged with a magnetic stir bar, Cul (28 mg, 0.15 mmol, 0.05 equiv.), K3PO4 (1.31 g, 6.17 mmol, 2.1 equiv.), 1,2,4-triazole (0.20 g, 2.94 mmol, 1.0 equiv.), and 1,10-phenanthroline (52 mg, 0.29 mmol, 0.1 equiv.). The tube was then evacuated and filled with argon. The evacuation/filling sequence was repeated two additional times. Under a counterflow of argon, 3-iodoaniline (0.42 mL, 3.53 mmol, 1.2 equiv.) and degassed 1,4-dioxane (1.5 mL) were added via syringe. The tube was placed in a preheated oil bath at 110 °C and the solution was stirred vigorously for 24 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (2-3 mL), filtered through a plug of Celite, and rinsed with EtOAc. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica gel using a gradient solvent system of PE/EtoAc from 90/10 to 70/30 to afford compound 25 (0.41 g, 87%) as a brown solid. Rf (CH2Ch/acetone 60/40) 0.49. Mp: 114 - 116 °C. 1H NMR (400 MHz, DMSO-de) 8 9.13 (s, 1H, CH), 8.17 (s, 1H, CH), 7.15 (t, J = 8.0 Hz, 1H, CH), 7.04 (t, J = 2.1 Hz, 1H, CH), 6.94 (ddd, J = 7.9 Hz, J = 2.1 Hz, J = 0.9 Hz, 1H, CH), 6.60 (ddd, J = 8.1 Hz, J = 2.2 Hz, J = 0.9 Hz, 1H, CH), 5.48 (brs, 2H, NH2). HRMS (EI-MS) m/z calcd. for C8H9N4 [M+H]+: 161.0822, found: 161.0820.

Example _____20: N-(3-(1 H-1,2,4-triazol-1 -¡l)phen¡l)-4-(5-methyl-7H-pyrrolo[2,3-d ]prírim¡n-4-¡l)-3,6-d¡hydro¡r¡d¡na-1(2H)-carboxamide (26)

The reaction was carried out as described in the general procedure using aniline 25 (40 mg, 0.25 mmol) and amine 4 (85 mg, 0.30 mmol, 1.2 equiv.) in THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Cl 2 /acetone from 90/10 to 40/60 to provide compound 26 (63 mg, 63%) as a white solid. Rf (CH 2 Ch /acetone 50/50) 0.21. Mp: 228 - 230 °C. 1H NMR (400 MHz, DMSO-de) 8 11.83 (brs, 1H, NH), 9.22 (s, 1H, CH), 8.90 (brs, 1H, NH), 8.65 (s, 1H, CH), 8.22 (s, 1H, CH), 8.13 - 8.06 (m, 1H, CH), 7.63 - 7.53 (m, 1H, CH), 7.45 - 7.39 (m, 2H, 2 x CH), 7.32 (s, 1H, CH), 6.18 - 5.99 (m, 1H, CH), 4.34 - 4.21 (m, 2H, CH2), 3.77 (t, J = 5.6 Hz, 2H, CH2), 2.77 - 2.64 (m, 2H, CH2), 2.28 - 2.18 (m, 3H, CH3). HRMS (EI-MS) m/z calcd. for C21H21N8 O[M+H]+: 401.1833, found: 401.1832.

3-(3-methoxyphenoxy)aniline (27)

An oven-dried microwave vial was charged with a magnetic stir bar, Cul (29 mg, 0.15 mmol, 0.05 equiv.), 2-picolinic acid (123 mg, 0.30 mmol, 0.10 equiv.), 3-aminophenol (0.39 g, 3.60 mmol, 1.2 equiv.), and K3PO4 (1.27 g, 3.60 mmol, 2.0 equiv.). The tube was then evacuated and filled with argon. The evacuation/filling sequence was repeated two additional times. Under a counterflow of argon, 3-iodoanisole (0.36 mL, 3.00 mmol, 1.0 equiv.) and DMSO (6 mL) were added via syringe. The tube was placed in a preheated oil bath at 80 °C and the reaction mixture was stirred vigorously for 24 h. The reaction mixture was cooled to room temperature. EtOAc (30 mL) and H2O (5 mL) were added and the mixture was stirred. The organic phase was separated and the aqueous phase was extracted twice with EtOAc (30 mL). The combined organic phases were dried over MgSO4 and filtered through a pad of silica gel. The filtrate was concentrated and the resulting residue was purified by column chromatography on silica gel using a gradient solvent system of cyclohexane/EtOAc from 100/0 to 90/10 to afford compound 27 (87 mg, 85%) as a brown oil. 1H NMR (250 MHz, CDCb) 8 7.23 (t, J = 8.2 Hz, 1H, CH), 7.11 (t, J = 8.0 Hz, 1H, CH), 6.70 - 6.60 (m, 3H, 3 x CH), 6.47 - 6.43 (m, 1H, CH), 6.41 (m, 1H, CH), 6.35 (m, 1H, CH), 3.78 (s, 3H, OCH3), 3.69 (brs, 2H, NH2). All spectral data corresponded to literature values as found in Maiti, D.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 17423-17429.

Example 21: 4-(5-met¡l-7H-pyrrolo[2,3-d]p¡r¡m¡d¡n-4-yl)-N-(4-phenoxy¡phen¡l) -3,6-d¡hydro¡r¡d¡n-1(2H)-carboxamide (28)

The reaction was carried out as described in the general procedure using aniline 27 (54 mg, 0.25 mmol) and amine 4 (85 mg, 0.30 mmol, 1.2 equiv.) in THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Cl 2 /acetone from 80/20 to 20/80 to afford compound 28 (63 mg, 55%) as a beige solid. Rf (CH 2 Ch /acetone 60/40) 0.21. Mp: degradation 132 °C. 1H NMR (400 MHz, DMSO-de) 811.91 (brs, 1H, NH), 8.68 (brs, 1H, NH), 8.66 (s, 1H, CH), 7.36 7.21 (m, 5H, 5 x CH), 6.71 (dd,J =8.3 Hz,J =2.4 Hz, 1H, CH), 6.65 - 6.52 (m, 3H, 3xCH), 6.09 - 6.02 (m, 1H, CH), 4.24 - 4.16 (m, 2H, CH2), 3.74 (s, 3H, OCH3), 3.71 (t, J = 5.5 Hz, 2H, CH2), 2.69 - 2.61 (m, 2H, CH2), 2.22 (s, 3H, CH3). HRMS (EI-MS) m/z calcd. for C26H26N5O3 [M+H]+: 456.2030, found: 456.2031.

Example 22: W-[3-(2-methoxy¡phen¡l)phen¡l]-4-(5-met¡l-7H-pyrrolo[2,3-d]pyr¡m¡d n-4-l)-3,6-dihydro-2H-pyrdina-1-carboxamide

The reaction was carried out as described in the general procedureHwith 2'-methoxy-[1,1'-phenyl]-3-amine (26 mg, 0.13 mmol) and amine4 (47 mg, 0.16 mmol, 1.2 equiv.) in THF (4 mL). The crude mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Cl2/acetone from 100/0 to 40/60 to provide 29 (43 mg, 72%) as a white solid. Rf (CH2Cl2/acetone 50/50) 0.18. Mp: degradation 205 °C. 1H NMR (250 MHz, DMSO-de) 8 11.83 (s, 1H, NH), 8.65 (s, 1H, CH), 8.62 (s, 1H, NH), 7.60 (s 1H, CH), 7.49 (d, J = 8.0 Hz, 1H, CH), 7.40 - 7.20 (m, 4H, 4 x CH), 7.18 - 6.95 (m, 3H, 3 x CH), 6.05 (s, 1H, CH), 4.27 - 4.19 (m, 2H, CH2), 3.86 - 3.63 (m, 5H, OCH3 CH2), 2.68 (s, 2H, CH2), 2.24 (s, 3H, CH3). HRMS (EI-MS) m/z calcd. for CH 6H26N5O2 [M+H]+: 440.2081, found: 440.2080.

Example 23: W-[3-(3-methoxy¡phen¡l)phen¡l]-4-(5-met¡l-7H-pyrrolo[2,3-d]pyr¡m¡d ¡n-4-¡l)-3,6-di¡hydro-2H-pyr¡dina-1-carboxamide (30)

The reaction was carried out as described in the general procedureHwith 3'-methoxy-[1,1'-phenyl]-3-amine (26 mg, 0.13 mmol) and amine4 (47 mg, 0.16 mmol, 1.2 equiv.) in THF (4 mL). The crude mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Ch/acetone from 100/0 to 40/60 to give 30 (47 mg, 78%) as a white solid. Rf (CH2Ch/acetone 50/50) 0.19. Mp: degradation 224 °C. 1H NMR (250 MHz, DMSO-de) 8 11.83 (s, 1H, NH), 8.68 (s, 1H, CH), 8.65 (s, 1H, NH), 7.81 (s, 1H, CH), 7.56 (d, J = 7.9 Hz, 1H, CH), 7.47-7.04 (m, 6H, 6 x CH), 6.94 (d, J = 8.1 Hz, 1H, CH), 6.07 (s, 1H, CH), 4.26 (s, 2H, CH2), 3.82 (s, 3H, CH3), 3.76 (t, J= 4.6 Hz, 2H, CH2), 2.70 (s, 2H, CH2), 2.25 (s, 3H, CH3). HRMS (EI-MS) m/z calcd. for C26H26N5O2 [M+H]+: 440.2081, found: 440.2083.

Example 24: W-[3-(4-methoxy¡phen¡l)phen¡l]-4-(5-met¡l-7H-pyrrolo[2,3-d]pyr¡m¡d n-4-l)-3,6-dihydro-2H-pyrdina-1-carboxamide (31)

The reaction was carried out as described in the general procedureHwith 4'-methoxy-[1,1'-phenyl]-3-amine (26 mg, 0.13 mmol) and amine4 (47 mg, 0.16 mmol, 1.2 equiv.) in THF (4 mL). The crude mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Ch/acetone from 100/0 to 40/60 to provide 31 (43 mg, 72%) as a white solid. Rf (CH2Ch/acetone 50/50) 0.25. Mp: degradation 252 °C. 1H NMR (250 MHz, DMSO-d6) 811.83 (s, 1H, NH), 8.65 (s, 2H, CH NH), 7.77 (s, 1H, CH), 7.60 - 7.45 (m, 3 H, 3xCH), 7.37 - 7.15 (m, 3 H, 3xCH), 7.03 (d, J = 8.8 Hz, 2H, CH), 6.06 (s, 1H, CH), 4.25 (s, 2H, CH2), 3.85 - 3.71 (m, 5H, OCH3 CH2), 2.69 (s, 2H, CH2), 2.25 (s, 3H, CH3). HRMS (EI-MS) m/z calcd. for C26H26N5O2 [M+H]+: 440.2081, found: 440.2082.

Example 25: 4-(5-met¡l-7H-p¡rrolo[2,3-d]p¡r¡m¡d¡n-4-¡l)-N-(3-p¡r¡d l)-3,6-dihydro-2H-pyridin-1-carboxamide (32)

The reaction was carried out as described in the general procedureHwith 3-aminopyridine (75 mg, 0.80 mmol) and amino4 (240 mg, 0.96 mmol, 1.2 eq.) in THF (12 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Cl2/MeOH from 100/0 to 95/5 to provide compound32 (162 mg, 60%) as a beige solid. Rf (CH2Ch/MeOH 90/10) 0.24. Mp: 170 °C. 1H NMR (400 MHz, MeOD-d4) 88.72 (brs, 1H, CH), 8.66 (s, 1H, CH), 8.22 (brs, 1H, CH), 8.07 - 8.00 (m, 1H, CH), 7.44 (dd, J = 8.4, 4.9 Hz, 1H, CH), 7.28 (brs, 1H, CH), 6.09 (s, 1H, CH), 4.36 - 4.31 (m, 2H, CH2), 3.87 (t, J = 5.6 Hz, 2H, CH2), 2.78 - 2.71 (m, 2H, CH2), 2.32 (s, 3H, CH3). HRMS (EI-MS): m/z calcd. for C18H19N6 O[M+H]+: 335.1615; found: 335.1617.

Example 26: 4-(5-met¡l-7H-pyrrolo[2,3-d]p¡r¡m¡d¡n-4-¡l)-N-(2-t¡en¡l )-3,6-dihydro-2H-pyridin-1-carboxamide (33)

The reaction was carried out as described in the general procedureGwith amine4 (550 mg, 2.19 mmol) in anhydrous CH2Cl2 (30 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Ch/acetone from 100/0 to 50/50 to provide compound33 (278 mg, 54%) as a beige solid. Rf (CH2Ch/acetone 50/50) 0.57. Mp: 241 - 143 °C. 1H NMR (400 MHz, MeOD-d4) 88.62 (s, 1H, CH), 7.28 (dd, J = 5.1, 3.2 Hz, 1H, CH), 7.25 - 7.21 (m, 2H, CH), 7.13 (dd, J = 5.1, 1.4 Hz, 1H, CH), 6.07 - 6.01 (m, 1H, CH), 4.27 (q, J = 2.9 Hz, 2H, CH2), 3.83 (t, J = 5.6 Hz, 2H, CH2), 2.76 - 2.68 (m, 2H, CH2), 2.30 (d, J = 1.2 Hz, 3H, CH3). HRMS (EI-MS): m/z calcd. for C17H18N5OS [M+H]+: 340.1227; found: 340.1227.

Example 27: 4-(5-met¡l-7H-pyrrolo[2,3-d]p¡r¡m¡d¡n-4-¡l)-N-tetral¡n-1-¡l -3,6-dihydro-2H-pyridine-1-carboxamide (34-rac and 35-R)

The reaction was carried out as described in the general procedureHwith 1,2,3,4-tetrahydro-1-naphthylamine as a racemic mixture or with the pure (R)-enantiomer (73 mg, 0.50 mmol) and the amine4(150 mg, 0.60 mmol, 1.2 eq.) in THF (7 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Ch/MeOH from 100/0 to 95/5 to afford compound34-rac(122 mg, 63%) or35-R(116 mg, 60%) as a beige solid in both cases. Traces of DIPEA were removed by washing the solid with water.Rf(CH2Ch/MeOH 95/5) 0.34. Mp: 170 °C. 1H NMR (400 MHz, MeOD-d4) 88.61 (s, 1H, CH), 7.31 -7.26 (m, 1H), 7.23 (d, J = 1.2 Hz, 1H), 7.16 - 7.03 (m, 3H), 6.00 (dt, J = 3.3, 1.7 Hz, 1H, CH), 5.06 (t, J = 6.4 Hz, 1H, CH), 4.19 (q, J = 3.0 Hz, 2H, CH2), 3.81 - 3.69 (m, 2H, CH2), 2.91 - 2.72 (m, 2H, CH2), 2.70 - 2.62 (m, 2H, CH2), 2.31 (d, J = 1.2Hz, 3H, CH3), 2.12 - 1.93 (m, 2H, CH2), 1.91 - 1.76 (m, 2H, CH2). HRMS (EI-MS): m/z calcd. for C23H26N5 O[M+H]+: 388.2132; found: 388.2131.

(4-methylsulfonylpiperazin-1-yl)-(3-nitrophenyl)methanone (170)

1-Methylsulfonylpiperazine (350 µl, 4.04 mmol, 1.5 equiv.) and Et3N (670 µl, 4.84 mmol, 1.8 equiv.) were suspended in DCM (15 mL). The solution was cooled to 0 °C and 3-nitrobenzoyl chloride (500 mg, 2.69 mmol, 1.0 equiv.) in 7.0 mL of DCM was added dropwise. The reaction was stirred at room temperature for 3 h and then washed with saturated NaHCO3 solution (30 mL) and 1 M HCl solution (30 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to give compound170 (684 mg, 81%) as a brown amorphous solid which was used without further purification in the next step. Rf (EP/AcOEt 20/80) 0.41 1H NMR (400 MHz, CDCl3) 8 (ppm) 8.35 - 8.31 (m, 1H, CH), 8.30 - 8.27 (m, 1H, CH), 7.79 - 7.74 (m, 1H, CH), 7.66 (t, J = 7.9 Hz, 1H, CH), 4.09 - 3.44 (m, 4H, 2 x CH2), 3.30 (brs, 4H, 2 x CH2), 2.83 (s, 3H, CH3). HRMS (EI-MS) m/z calcd. for C12H16N3O5S [M+H]+: 314.0803, found: 314.0805.

(3-aminophenyl)-(4-methylsulfonylpiperazin-1-yl)methanone (171)

Tin chloride (1.51 g, 7.95 mmol, 5.0 equiv.) was added to a solution of compound 170 in ethanol (15 mL). The reaction was heated to 80 °C for 6 h. The solvent was then concentrated under reduced pressure, water was added and the pH was corrected to about 12 with 2 M NaOH solution. The resulting solid was filtered over diatomaceous earth and the recovered filtrate was extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over MgSO 4 , filtered and concentrated under reduced pressure to give compound 171 (303 mg, 67%) as a brown oil which was used without further purification in the next step. Rf (CH 2 Ch / acetone 50/50) 0.27. 1H NMR (400 MHz, CDCb) 8 (ppm) 7.18 (t, J = 7.7 Hz, 1H, CH), 6.76 - 6.68 (m, 3H, 3 x CH), 3.94 - 3.49 (m, 6H, NH2 2 x CH2), 3.23 (brs, 4H, 2 x CH2), 2.80 (s, 3H, CH3). HRMS (EI-MS) m/z calcd. for C12H18N3O5S [M+H]+: 284.1066, found: 284.1063.

Examples 27-1: 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-[3-(4-methylsulfonylpiperazin-1-carbonyl)phenyl]-3,6- dihydro-2H-pyridine-1-carboxamide (172)

The reaction was carried out as described in the general procedure H with aniline 171 (150 mg, 0.53 mmol), 4-nitrophenyl chloroformate (128 mg, 0.64 mmol, 1.2 equiv.), DIPEA (190 µl, 1.11 mmol, 2.1 equiv.) and amine 4 (159 mg, 0.64 mmol, 1.2 equiv.) in dry THF (7.6 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM/acetone from 100/0 to 20/80 to provide compound 172 (143 mg, 52%) as a beige solid. Rf (CH 2 Ch /acetone 30/70) 0.29 Mp: 140 - 142 °C. 1H NMR (400 MHz, MeOD-d4) 8.63 (s, 1H, CH), 7.59 (t, J= 1.9 Hz, 1H, CH), 7.51 (ddd, J = 8.2, 2.3, 1.1 Hz, 1H, CH), 7.40 (t, J= 7.9 Hz, 1H, CH), 7.24 (d, J = 1.3 Hz, 1H, CH), 7.11 (dt, J = 7.5, 1.3 Hz, 1H, CH), 6.08 -6.03 (m, 1H, CH), 4.31 (q, J = 2.8 Hz, 2H, CH2), 3.86 (t, J = 5.6 Hz, 2H, CH2), 3.95 - 3.54 (m, 4H, 2 x CH2), 3.37 - 3.20 (m, 4H, 2 x CH2), 2.88 (s, 3H, CH3), 2.78 - 2.71 (m, 2H, CH2), 2.31 (d, J = 1.2 Hz, 3H, CH3). HRMS (EI-MS) m/z calcd. for C25H30N7O4S [M+H]+: 524.2068, found: 524.2075.

W-[3-(3-bromophenoxy)propyl]carbamate tert-butyl (36)

To a solution of 3-bromophenol (600 mg, 3.47 mmol) in THF (12 mL) was added tert-butyl W-(3-hydroxypropyl)carbamate (912 mg, 5.20 mmol, 1.5 equiv.) and triphenylphosphine (1.0 g, 3.81 mmol, 1.1 equiv.) in THF (5 mL) in a microwave tube. A solution of DIAD (768 mg, 3.81 mmol, 1.1 equiv.) in THF (5 mL) was added dropwise, the tube was sealed, and the mixture was heated in the microwave at 120 °C for 1 h. After cooling, additional triphenylphosphine and DIAD (1 equiv.) were added and the tube was heated at 120 °C for 30 min. The mixture was concentrated and the residue was taken up in EtOAc, washed with saturated NaCl solution (30 mL), dried over MgSO<4>and concentrated under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of EP/Et<2>O from 100/0 to 50/50 to afford compound36(874 mg, 77%) as a white solid. Rf(EP/Et<2>O 50/50) 0.51. Mp: 77 - 79 °C.<1>H NMR (400 MHz, CDCb) 57.18 - 7.01 (m, 3H, 3 x CH), 6.85 - 6.79 (m, 1H, CH), 4.72 (s, 1H, NH), 4.00 (t, J = 6.2 Hz, 2H, CH<2>), 3.31 (q, J = 6.3 Hz, 2H, CH<2>), 1.97 (p, J = 6.2 Hz, 2H, CH<2>), 1.44 (s, 9H, 3 x CH<3>). HRMS (EI-MS) m/z calcd. for CuH<21>BrNO<3>[M+H]<+>: 330.0699, found: 330.0695.

Tert-butyl N-[3-[3-(3-nitrophenyl)phenoxy]propyl]carbamate (37)

Compound 36 (300 mg, 0.91 mmol), 3-phenylboronic acid (304 mg, 1.82 mmol, 2.0 equiv.) and K<2>CO<3> (377 mg, 2.73 mmol, 3.0 equiv.) were suspended in a mixture of DME/EtOH/H<2>O (1.8 mL, 1.2 mL and 0.6 mL). The solution was degassed for 20 min under Ar and Pd(PPh<3>)<4> (53 mg, 0.045 mmol, 0.05 equiv.) was added. The reaction was heated in the microwave at 160 °C for 15 min. After cooling, the mixture was extracted with CH<2>Cl<2> (3 x 10 mL). The combined organic phases were dried (MgSO<4>), filtered and evaporated under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of Ep/Et<2>O from 100/0 to 70/30 to afford compound 37 (267 mg, 79%) as a yellow solid. Rf(EP/Et<2>O 80/20) 0.26. Mp: 93 - 95 °C.<1>H NMR (400 MHz, MeOD-d<4>) 58.41 (t, J = 1.9 Hz, 1H, CH), 8.20 (ddd, J = 8.2, 2.2, 0.8 Hz, 1H, CH), 8.03 - 7.98 (m, 1H, CH), 7.67 (t, J = 8.0 Hz, 1H, CH), 7.39 (t, J = 7.9 Hz, 1H, CH), 7.24 (d, J = 7.7 Hz, 1H, CH), 7.22 - 7.19 (m, 1H, CH), 6.99 (dd, J = 8.2, 1.8 Hz, 1H, CH), 4.09 (t, J = 6.2Hz, 2H, CH<2>), 3.26 (t, J = 6.8 Hz, 2H, CH<2>), 1.97 (p, J = 6.5 Hz, 2H, CH<2>), 1.42 (s, 9H, 3 x CH<3>). HRMS (EI-MS) m/z calcd. for C<20>H<24>N<2>O<5>[M+Na]<+>395.1577, found: 395.1575.

N-[3-[3-(3-nitrophenyl)phenoxy]propyl]acetamide (38)

A solution of 4 N HCl in dioxane (1.10 mL, 4.3 mmol, 8.0 equiv) was added to the Boc-protected amine 37 (200 mg, 0.54 mmol) in CH < 2 > Cl < 2 > (2 mL) at 0 °C under argon. The reaction was stirred for 2 h at room temperature or until complete (TLC). The solvent was then evaporated and the residue was suspended in CH < 2 > Cl < 2 > (5 mL) and saturated K < 2 > CO < 3 > solution was added to pH 8-9. The mixture was stirred for 30 min and extracted with CH < 2 > Cl < 2 > (2 x 5 mL). The combined organic layers were dried over MgSO < 4 >, filtered and concentrated under reduced pressure to afford the desired product which was used without further purification in the next step.

The free amine was then placed in a round bottom flask under Ar, diluted with anhydrous CH<2>Cl<2> (<2 mL>) and cooled to 0 °C. Triethylamine (38 μl, 0.28 mmol, 1.5 equiv.) was added followed by acetic anhydride (0.26 mL, 2.69 mmol, 5 equiv.) and the mixture was heated at 40 °C for 2 h. The reaction was then quenched with Na<2>CO<3> and the aqueous layer was extracted with AcOEt (3 x 10 mL). The combined organic layers were washed with brine, dried over MgSO<4> and the solvent was removed under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Ch/MeOH from 100/0 to 95/5 to provide compound 38 (139 mg, 82%) as a yellow solid. Rf (CH2Ch/MeOH 95/5) 0.48. 1H NMR (400 MHz, MeOD-d4) 88.37 (t, J = 2.0 Hz, 1H, CH), 8.21 - 8.13 (m, 1H, CH), 8.00 - 7.94 (m, 1H, CH), 7.64 (t, J = 8.0 Hz, 1H, CH), 7.37 (t, J = 7.9 Hz, 1H, CH), 7.24 - 7.15 (m, 1H, CH), 7.17 (t, J = 2.1 Hz, 1H, CH), 6.97 (dd, J = 8.3, 2.4 Hz, 1H, CH), 4.08 (t, J = 6.1 Hz, 2H, CH2), 3.37 (t, J = 6.9 Hz, 2H, CH2), 1.99 (p, J = 6.6 Hz, 2H, CH2), 1.94 (s, 3H, CH3). HRMS (EI-MS): m/z calcd. for C17H19N2O4 [M+H]+: 315.1339; found 315.1334.

W-(3-((3'-amino-[1,1'-biphenyl]-3-yl)oxy)propyl)acetamide (39)

Pd/C (10 wt%) (5 mg, 0.04 mmol, 0.1 equiv.) was added to a solution of the nitro compound38(133 mg, 0.42 mmol) in AcOEt (12 mL) in a small hydrogenation reactor. The reaction was stirred under 15 bar H2 pressure until completion. The mixture was then filtered through a pad of Celite which was rinsed several times with MeOH. The solvent was evaporated under reduced pressure to give the desired amine39(101 mg, 84%) as a yellow oil which was used in the next step without further purification. Rf (CH2Ch/MeOH 90/10) 0.19. 1H NMR (400 MHz, MeOD-d4) 87.27 (t, J = 7.9 Hz, 1H, CH), 7.18 - 7.07 (m, 3H, CH), 6.96 (t, J = 2.0 Hz, 1H, CH), 6.93 - 6.88 (m, 1H, CH), 6.88 - 6.83 (m, 1H, CH), 6.72 - 6.67 (m, 1H, CH), 4.03 (t, J = 6.1 Hz, 2H, CH2-4), 3.35 (t, J = 6.9 Hz, 2H, CH2-2), 2.00 - 1.94 (m, 2H, CH2-3), 1.93 (s, 3H CH3). HRMS (EI-MS): m/z calcd. for C17H21N2O2 [M+H]+: 285.1598; found 285.1595.

IV-[3-[3-(3-nitrophenyl)phenoxy]propyl]methanesulfonamide (173)

A solution of 4 N HCl in dioxane (1.10 mL, 4.3 mmol, 8.0 equiv) was added to the Boc-protected amine (200 mg, 0.54 mmol) in CH Cl (2 mL) at 0 °C under argon. The reaction was stirred for 2 h at room temperature or until complete (TLC). The solvent was then evaporated and the residue was suspended in CH Cl (5 mL) and saturated K CO solution was added to pH 8-9. The mixture was stirred for 30 min and extracted with CH Cl (2 × 5 mL). The combined organic layers were dried over MgSO , filtered, and concentrated under reduced pressure to afford the desired product which was used without further purification in the next step.

The free amine was then placed in a round bottom flask under Ar and diluted with anhydrous CH2Cl2 (2 mL). Triethylamine (38 µl, 0.28 mmol, 1.5 equiv.) was added followed by methanesulfonyl chloride (47 µl, 0.61 mmol, 1.1 equiv.) and the reaction was stirred at room temperature overnight. The reaction was then quenched with 0.1 M HCl (15 mL) and the aqueous layer was extracted with AcOEt (3 x 10 mL). The combined organic layers were washed with brine, dried over MgSO4 and the solvent was removed under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Ch/MeOH from 100/0 to 98/2 to provide compound 173 (132 mg, 69%) as a yellow solid. Rf (CH2Ch/MeOH 90/10) 0.75. 1H NMR (400 MHz, MeOD-d4) 88.30 (t, J = 2.0 Hz, 1H, CH), 8.11 (ddd, J = 8.1,2.2, 1.0 Hz, 1H, CH), 7.91 (ddd, J = 7.8, 1.7, 0.9 Hz, 1H, CH), 7.59 (t, J = 8.0 Hz, 1H, CH), 7.33 (t, J = 7.9 Hz, 1H, CH), 7.17 - 7.10 (m, 2H, 2 x CH), 6.98 - 6.91 (m, 1H, CH), 4.10 (t, J = 6.1 Hz, 2H, CH2), 3.28 (t, J = 6.8 Hz, 2H, CH2), 2.94 (s, 3H, CH3), 2.02 (p, J= 6.5 Hz, 2H, CH2). HRMS (EI-MS) m/z calcd. for C16H19N2O5S [M+H]+: 351.1009, found: 351.1007.

N-[3-[3-(3-aminophenyl)phenoxy]propyl]methanesulfonamide (174)

Hydrazine monohydrate (14 pl, 0.29 mmol, 0.2 equiv.) and Fe(acac)3 (1.3 mg, 0.25 mol%) were added to a solution of compound173 (512 mg, 1.46 mmol) in methanol (1.5 mL) in a sealed tube. The reaction was then heated to 130 °C for 15 min. After cooling, the crude product was filtered over diatomaceous earth and the filtrate was evaporated under reduced pressure to give the amine174 (289 mg, 62%) as a brown oil which was used without further purification in the next step. Rf (CH2Ch/MeOH 80/20) 0.49. 1H NMR (400 MHz, MeOD-d4) 8 (ppm) 7.29 (t, J = 7.9 Hz, 1H, CH), 7.19 - 7.09 (m, 3H, CH), 6.99 - 6.96 (m, 1H, CH), 6.94 - 6.86 (m, 2H, CH), 6.74 - 6.69 (m, 1H, CH), 4.12 (t, J = 6.0 Hz, 2H, CH2), 3.28 (t, J = 6.8 Hz, 2H, CH2), 2.93 (s, 3H, CH3), 2.03 (p, J = 6.5 Hz, 2H, CH2). HRMS (EI-MS) m/z calcd. for C16H21N2O5S [M+H]+: 321.1269, found: 321.1267.

Example 28: N-(3'-(3-acetamidopropoxy)-[1,1'-biphenyl]-3-yl)-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4- yl)-5,6-dihydropyridin-1(2H)-carboxamide (40)

The reaction was carried out as described in the general procedureHwith aniline39(97 mg, 0.34 mmol) and amine4(94 mg, 0.38 mmol, 1.1 eq.) in THF (5 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Ch/MeOH from 100/0 to 90/10 to provide compound 40 (74 mg, 40%) as a beige solid. Rf (CH2Ch/MeOH 90/10) 0.18. 1H NMR (400 MHz, MeOD-d4) 8.64 (s, 1H, CH), 7.71 (brs, 1H, CH), 7.46 - 7.23 (m, 5H, 5 x CH), 7.22 - 7.14 (m, 2H, 2 x CH), 6.93 - 6.86 (m, 1H, CH), 6.07 (brs, 1H, CH2), 4.32 (d, J = 2.0 Hz, 2H, CH2), 4.08 (t, J = 6.2 Hz, 2H, CH2), 3.86 (t, J = 5.6 Hz, 2H, CH2), 3.37 (t, J = 6.9 Hz, 2H, CH2), 2.74 (brs, 2H, CH2), 2.31 (s, 3H, CH3), 2.03 - 1.96 (m, 2H, CH2), 1.94 (s, 3H, CH3). HRMS (EI-MS): m/z calcd. for C30H33N6O3 [M+H]+: 525.2609; found: 525.2611.

Example 28-1: N-[3-[3-[3-(methanesulfonamido)propoxy]phenyl]phenyl]-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 3,6-dihydro-2H-pyridine-1-carboxamide (175)

The reaction was carried out as described in the general procedure H with aniline 174 (273 mg, 0.85 mmol), 4-nitrophenyl chloroformate (205 mg, 1.02 mmol, 1.2 equiv.), DIPEA (310 µl, 1.79 mmol, 2.1 equiv.) and amine 4 (255 mg, 1.02 mmol, 1.2 equiv.) in dry THF (12.0 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM/acetone from 100/0 to 20/80 to provide compound 174 (283 mg, 59%) as a beige solid. Rf (CH 2 Ch /acetone 50/50) 0.24. Mp: 114 - 116 °C 1H NMR (400 MHz, MeOD-d4) 8 (ppm) 8.63 (s, 1H, CH), 7.89 (s, 0.65H, NH), 7.71 (s, 1H, CH), 7.46 - 7.15 (m, 7H, 7 x CH), 6.97 - 6.88 (m, 1H, CH), 6.05 (brs, 1H, CH), 4.35 - 4.29 (m, 2H, CH2), 4.14 (t, J = 6.1 Hz, 2H, CH2), 3.87 (t, J = 5.6 Hz, 2H, CH2), 3.28 (t, J= 6.9 Hz, 2H, CH2), 2.93 (s, 3H, CH3), 2.77 - 2.72 (m, 2H, CH2), 2.31 (s, 3H, CH3), 2.04 (p, J = 6.5 Hz, 2H, CH2). HRMS (EI-MS) m/z calcd. for C29H33N6O4S [M+H]+: 561.2286, found: 561.2279.

3-[4-(dimethylamino)phenoxy]aniline (41)

An oven-dried screw-capped test tube was charged with a magnetic stir bar, copper(I) iodide (28 mg, 0.15 mmol, 0.1 equiv.), 2-picolinic acid (36 mg, 0.30 mmol, 0.2 equiv.), 4-bromo-N,N-dimethylaniline (300 mg, 1.5 mmol), 3-aminophenol (196 mg, 1.80 mmol, 1.2 equiv.), and K3PO4 (636 mg, 3.00 mmol, 2 equiv.). The tube was then evacuated and refilled with argon. The evacuation/filling sequence was repeated two more times. Under a counterflow of argon, dimethyl sulfoxide (5 mL) was added via syringe. The tube was placed on a preheated plate at 90 °C and the reaction mixture was stirred vigorously for 24 h. The reaction mixture was then cooled to room temperature. Ethyl acetate and water were added and the mixture was stirred. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2 x 25 mL). The combined organic phases were dried over MgSO4 and filtered, and the mixture was concentrated under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of Ep/AcOEt (100/0 to 80/20). The product was then precipitated with pentane to give aniline41 (0.181 g, 53%) as a beige amorphous solid. 1H NMR (250 MHz, CDCb) 87.07 (t, J = 8.0 Hz, 1H, CH), 7.02-6.95 (m, 2H, 2 x CH), 6.80-6.72 (m, 2H, 2 x CH), 6.36 (dd, J = 8.1, 2.3 Hz, 2H, 2 x CH), 6.27 (t, J = 2.0 Hz, 1H, CH) 3.66 (brs, 2H, NH2), 2.96 (s, 6H, 2 x CH3)2). HRMS (EI-MS): m/z calcd. for C14H17N2O [M+H]+ 229.1335; found: 229.1338.

Example_____29: W-[3-[4-(dimethylamino)phenoxy]phenyl]-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydro-2H- pyridine-1-carboxamide (42)

The reaction was carried out as described in general procedure H with the prepared aniline derivative 41 (66 mg, 0.29 mmol) and the amine 4 (100 mg, 0.35 mmol, 1.2 equiv.) in THF (4 mL). The crude mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch /acetone from 100/0 to 50/50. The product was then precipitated with pentane to afford 42 (57 mg, 42%) as a beige amorphous solid. 1H NMR (250 MHz, DMSO) 811.82 (s, 1H, NH), 8.64 (s, 1H, CH), 8.60 (s, 1H, NH), 7.31 (s, 1H, CH), 7.26 - 7.08 (m, 3H, 3 x CH), 7.00 - 6.85 (m, 2H, 2 x CH), 6.82 - 6.69 (m, 2H, 2 x CH), 6.57 - 6.44 (m, 1H, CH), 6.02 (s, 1H, CH), 4.18 (s, 2H, CH2), 3.69 (s, 2H, CH2), 2.87 (s, 6H, 2 x CH3), 2.65 (s, 2H, CH2), 2.22 (s, 3H, CH3). HRMS (EI-MS): m/z calcd. for C27H28N6O2 [M+H]+: 469.2347; found: 469.2341.

3-(3-aminophenoxy)-N,N-dimethylaniline (176)

An oven-dried microwave reaction vial was charged with 3-aminophenol (196 mg, 1.80 mmol, 1.2 equiv.), Cul (29 mg, 0.15 mmol, 10 mol%), 2-picolinic acid (37 mg, 0.30 mmol, 20 mol%), and KPO (637 mg, 3.00 mmol, 2.0 equiv.). It was then evacuated and back-filled with argon 3 times, then 3-bromo-N,N-dimethylaniline (300 mg, 1.50 mmol, 1.0 equiv.) and dry DMSO (3.0 mL) were added under argon, and the reaction mixture was stirred at 90 °C on a preheated plate for 24 h. The reaction mixture was diluted with H2O (25 mL) and EtOAc (25 mL), the aqueous phase was separated and extracted with EtOAc (3 x 20 mL) and then with the combined organic layers. The organic layers were washed with brine (3 x 15 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of PE/EtOAc from 100 to 80/20 to afford compound 176 (166 mg, 49%) as a brown oil. Rf (PE/EtOAc 90/10) 0.19. 1H NMR (250 MHz, CDCb) 87.17 (t, J = 8.1 Hz, 1H, CH), 7.08 (t, J = 8.0 Hz, 1H, CH) 6.48 (ddd, J = 8.2, 2.5, 0.8 Hz, 1H, CH), 6.45 - 6.30 (m, 5H, 5 x CH), 3.66 (s, 2H, NH2), 2.93 (s, 6H, 2 x CH3). HRMS (EI-MS) m/z calcd. for C14H17N2 O[M+H]+: 229.1335, found: 229.1338.

Example_____ 94: N-(3-(3-(dimethylamino)phenoxy)phenyl)-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridin-1 (2H)-carboxamide (177)

The reaction was carried out as described in the general procedure H with aniline 176 (78 mg, 0.34 mmol, 1.0 equiv.), 4-nitrophenyl chloroformate (83 mg, 0.41 mmol, 1.2 equiv.), DIPEA (143 pl, 0.82 mmol, 2.4 equiv.) and amine 4 (103 mg, 0.41 mmol, 1.2 equiv.) in dry THF (5 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM/MeOH from 100 to 95/5 to provide compound 177 (124 mg, 78%) as a brown solid. Rf (DCM/MeOH 95/5) 0.38. Mp: 114 -116 °C. 1H NMR (250 MHz, DMSO-d6) 811.82 (s, 1H, NH7), 8.64 (s, 2H, NH CH-2), 7.35 - 7.10 (m, 5H, CH-6 4 x CH), 6.58 (ddd, J = 7.6, 2.4, 1.4 Hz, 1H, CH), 6.49 (ddd, J = 8.5, 2.5, 0.8 Hz, 1H, CH), 6.37 (t, J = 2.3 Hz, 1H, CH), 6.24 (ddd, J = 8.0, 2.2, 0.8 Hz, 1H, CH), 6.03 (brs, 1H, CH), 4.19 (d, J = 3.0 Hz, 2H, CH2), 3.71 (t, J = 5.5 Hz, 2H, CH2), 2.88 (s, 6H, 2 x CH<3>), 2.66 (brs, 2H, CH<2>), 2.22 (d,J =1.1 Hz, 3H, CH<3>). HRMS (EI-MS) m/z calcd. for C<27>H<29>N<6>O<2>[M+H]<+>: 469.2347, found: 469.2348.

1 -(2-bromoethoxy)-3-nitrobenzene (178)

The reaction was carried out as described in the general procedure using 3-nitrophenol (500 mg, 3.59 mmol, 1.0 equiv.), 1,2-dibromoethane (2.47 mL, 28.70 mmol, 8.0 equiv.) and K<2>CO<3>(794 mg, 5.74 mmol, 1.6 equiv.) in dry MeCN (4.5 mL) for 9 h. The crude residue was purified by silica gel column chromatography using a solvent gradient of PE/EtOAc system from 100 to 95/5 to afford compound 178 (698 mg, 79%) as a yellow solid. Rf (PE/EtOAc 90/10) 0.50. <1>H NMR (250 MHz, DMSO-d<a>) 57.84 (ddd, J = 8.1, 2.2, 1.0 Hz, 1H, CH), 7.74 (t, J = 2.3 Hz, 1H, CH), 7.60 (t, J = 8.2 Hz, 1H, CH), 7.45 (ddd, J = 8.3, 2.5, 1.0 Hz, 1H, CH), 4.58 - 4.37 (m, 2H, CH<2>), 3.92 - 3.77 (m, 2H, CH<2>). All spectral data corresponded to literature values as found in Kawamoto M. et al., Chem. Commun., 2010, 46, 8344-8346.

1 -methyl-4-(2-(3-nitrophenoxy)ethyl)piperazine (180)

The reaction was carried out as described in the general procedureUsing alkyl halide 178 (406 mg, 1.65 mmol, 1.0 equiv.) and 1-methylpiperazine (568 µl, 5.12 mmol, 3.1 equiv.) in dry THF (9 mL) for 24 h to provide compound180 (362 mg, 83%) as a beige solid.<1>H NMR (250 M<h z>, CDC<b>) 5 7.81 (ddd, J = 8.1, 2.1, 1.0 Hz, 1H, CH), 7.74 (t, J = 2.3 Hz, 1H, CH), 7.41 (t, J = 8.2 Hz, 1H, CH), 7.22 (ddd, J = 8.3, 2.5, 1.0 Hz, 1H, CH), 4.17 (t, J = 5.7 Hz, 2H, CH<2>), 2.84 (t, J = 5.7 Hz, 2H, CH<2>), 2.62 (brs, 4H, 2 x CH<2>), 2.47 (brs, 4H, 2 x CH<2>), 2.29 (s, 3H, CH<3>). All spectral data correspond to literature values as found in Lee S. et al., J. Med Chem., 2020, 63, 3908–3914.

3-(2-(4-methylpiperazin-1-yl)ethoxy)aniline (182)

The reaction was carried out as described in the general procedureN using nitro180 (315 mg, 1.19 mmol, 1.0 equiv.) and 10 wt% Pd/C (128 mg, 0.12 mmol, 0.1 equiv.) in MeOH (7 mL) for 2 h to provide compound182 (261 mg, 93%) as a yellow oil. This product was used without further purification in the next step.<1>H NMR (250 MHz, DMSO-d<a>) 56.87 (t, J = 8.3 Hz, 1H, CH), 6.28 - 6.00 (m, 3H, 3 x CH), 5.00 (brs, 2H, NH<2>), 3.94 (t, J= 5.9 Hz, 2H, CH<2>), 2.63 (t, J= 5.9 Hz, 2H, CH<2>), 2.46 (brs, 4H, 2 x CH<2>), 2.31 (brs, 4H, 2 x CH<2>), 2.14 (s, 3H, CH<3>). HRMS (EI-MS) m/z calcd. for C<13>H<22>N<3>O[M+H]<+>: 236.1757, found: 236.1760.

Example 95: 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(3-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-3 ,6-dihydropyridine-1(2H)-carboxamide (184)

The reaction was carried out as described in General Procedure H with aniline182 (81 mg, 0.34 mmol, 1.0 equiv.), 4-nitrophenyl chloroformate (83 mg, 0.41 mmol, 1.2 equiv.), DIPEA (144 pl, 0.83 mmol, 2.4 equiv.) and amine4 (104 mg, 0.41 mmol, 1.2 equiv.) in dry THF (5 mL). The crude reaction mixture was purified by column chromatography on silica gel using a gradient solvent system of DCM/MeOH/NH<4>OH from 100 to 80/20/1, followed by preparative TLC using DCM/MeOH/NH<4>OH 80/20/1 solvent system to provide compound 184 (24 mg, 15%) as a pale orange solid.

Rf (DCM/MeOH/NH<4>OH 90/10/1) 0.34. Mp: degradation 111 °C.<1>H NMR (250 MHz, DMSO-d<6>) 5 11.83 (s, 1H, NH), 8.64 (s, 1H, NH), 8.54 ( s, 1H, CH), 7.33 - 7.30 (m, 1H, CH), 7.25 - 7.01 (m, 3H, 3 x CH), 6.52 (dt, J = 7.4, 2.3 Hz, 1H, CH), 6.08 - 6.02 (m, 1H, CH), 4.21 (d, J= 2 .8 Hz, 2H, CH<2>), 4.02 (t, J = 5.8 Hz, 2H, CH<2>), 3.72 (t, J = 5.6 Hz, 2H, CH<2>), 2.68 (t, J = 5.6 Hz, 4H, 2 x CH<2>), 2.52-2.49 (m, 4H, 2 x CH<2>), 2 .37 (brs, 4H, 2 x CH<2>), 2.24 (d, J = 1.1 Hz, 3H, CH<3>), 2.18 (s, 3H, CH<3>). HRMS (EI-MS) m/z calcd. for C<26>H<34>N</>O<2>[M+H]<+>: 476.2768, found: 476.2768.

1 -(3-bromopropoxy)-3-nitrobenzene (179)

The reaction was carried out as described in the general procedure using 3-nitrophenol (500 mg, 3.59 mmol, 1.0 equiv.), 1,3-dibromopropane (2.91 mL, 28.70 mmol, 8.0 equiv.) and K<2>CO<3>(794 mg, 5.74 mmol, 1.6 equiv.) in dry MeCN (4.5 mL) for 56 h. The crude reaction mixture was purified by silica gel column chromatography using PE/DCM 70/30 to afford compound 179 (634 mg, 68%) as a yellow oil. Rf (PE/EtOAc 90/10) 0.45.<1>H NMR (250 MHz, CDCb) 57.84 (ddd, J = 8.1, 2.2, 1.0 Hz, 1H, CH), 7.74 (t, J = 2.3 Hz, 1H, CH), 7.44 (t, J = 8.2 Hz, 1H, CH), 7.23 (ddd, J = 8.3, 2.6, 1.0 Hz, 1H, CH), 4.20 (t, J= 5.8 Hz, 2H, CH<2>), 3.62 (t, J= 6.3 Hz, 2H, CH2), 2.36 (p, J = 6.1 Hz, 2H, CH2). HRMS (EI-MS) m/z calcd. for C9HiiBrNO3 [M+H]+: 259.9917, found: 259.9915.

1 -methyl-4-(3-(3-nitrophenoxy)propyl)piperazine (181)

The reaction was carried out as described in the general procedureUsing alkyl halide179(400 mg, 1.54 mmol, 1.0 equiv.), 1-methylpiperazine (530 µl, 4.77 mmol, 3.1 equiv.) in dry THF (9 mL) for 56 h to provide compound181(369 mg, 86%) as a yellow oil. 1H NMR (250 MHz, CDCI3) 5 7.80 (ddd, J = 8.1, 2.1, 1.0 Hz, 1H, CH), 7.72 (t, J = 2.3 Hz, 1H, CH), 7.40 (t, J = 8.2 Hz, 1H, CH), 7.21 (ddd, J = 8.3, 2.5, 1.0 Hz, 1H, CH), 4.09 (t, J = 6.3 Hz, 2H, CH2), 2.60 - 2.38 (m, 10H, 5 x CH2), 2.29 (s, 3H, CH3), 2.01 (p, 2H, CH2). HRMS (EI-MS) m/z calcd. for C14H22N3O3 [M+H]+: 280.1656, found: 280.1655.

3-(3-(4-methylpiperazin-1-yl)propoxy)aniline (183)

The reaction was carried out as described in the general procedureN using nitro compound181 (276 mg, 0.99 mmol, 1.0 equiv.) and 10 wt% Pd/C (105 mg, 0.01 mmol, 0.1 equiv.) in MeOH (5.5 mL) for 2 h to provide compound183 (208 mg, 85%) as a beige solid. Mp: 54 - 56 °C. 1H NMR (400 MHz,<c>D<c>I3) 5 7.04 (t, J = 8.0 Hz, 1H, CH), 6.29 (ddd, J = 15.3, 8.0, 2.2 Hz, 2H, 2 x CH), 6.24 (t, J = 2.3 Hz, 1H, CH), 3.96 (t, J = 6.4 Hz, 2H, CH2), 3.63 (s, 2H, NH2), 2.76 - 2.33 (m, 10H, 5 x CH2), 2.29 (s, 3H, CH3), 1.94 (p, J = 6.7 Hz, 1H, CH2). HRMS (EI-MS) m/z calcd. for C14H24N3 O[M+H]+: 250.1914, found: 250.1916.

Example 96: 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(3-(3-(4-methylpiperazin-1-yl)propoxy)phenyl)-3 ,6-dihydropyridine-1(2H)-carboxamide (185)

The reaction was carried out as described in the general procedure H with aniline 183 (178 mg, 0.71 mmol, 1.0 equiv.), 4-nitrophenyl chloroformate (173 mg, 0.86 mmol, 1.2 equiv.), DIPEA (448 pl, 2.57 mmol, 2.4 equiv.) and amine 4 (246 mg, 0.86 mmol, 1.2 equiv.) in dry THF (10 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM/MeOH/NH 4 OH from 100 to 90/10/1 to provide compound 185 (77 mg, 22%) as a beige solid. Rf (DCM/MeOH/NH 4 OH 90/10/1) 0.46. Mp: 102 - 104 °C. 1H NMR (250 MHz, DMSO-da) 511.83 (s, 1H, NH), 8.64 (s, 1H, CH), 8.54 (s, 1H, NH), 7.36 - 7.27 (m, 1H, 1H, CH), 7.20 (t, J = 2.1 Hz, 1H, CH), 7.17 - 7.03 (m, 2H, 2 x CH), 6.50 (dt, J = 7.5, 2.0 Hz, 1H, CH), 6.09 - 6.00 (m, 1H, CH), 4.27 - 4.16 (m, 2H, CH2), 3.94 (t, J = 6.4 Hz, 2H, CH2), 3.72 (t, J = 5.6Hz, 2H, CH2), 2.72 - 2.63 (m, 2H, CH2), 2.49 - 2.27 (m, 10H, 5 x CH2), 2.24 (d, J = 1.1 Hz, 3H, CH3), 2.17 (s, 3H, CH3), 1.85 (p, J= 6.7 Hz, 2H, CH2). HRMS (EI-MS) m/z calcd. for C27H36N7O2 [M+H]+: 490.2925, found: 490.2922.

(3-(3-nitrophenoxy)propyl)carbamate tert-butyl (186)

The reaction was carried out as described in the general procedure using 3-nitrophenol (200 mg, 1.44 mmol, 1.0 equiv.), 3-(Boc-amino)-1-propanol (492 pl, 2.88 mmol, 2.0 equiv.), pH 3 (642 mg, 2.45 mmol, 1.7 equiv.) and DIAD (0.482 mL, 2.45 mmol, 1.7 equiv.) in dry THF (5 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of PE/EtOAc from 95/5 to 80/20 to provide compound 186 (412 mg, 96%) as a yellow oil. Rf (PE/EtOAc 80/20) 0.33. 1H R<m>N (250 MHz, CDCI3) 57.82 (ddd, J= 8.1, 2.1, 1.0 Hz, 1H, CH), 7.72 (t, J = 2.3 Hz, 1H, CH), 7.43 (t, J = 8.2 Hz, 1H, CH), 7.22 (ddd, J = 8.3, 2.6, 1.0 Hz, 1H, CH), 4.69 (s, 1H, NH), 4.10 (t, J = 6.0 Hz, 2H, CH2), 3.34 (q, J = 6.6 Hz, 2H, CH2), 2.02 (p, J = 6.4 Hz, 2H, CH2), 1.44 (s, 9H, 3 x CH3). HRMS (EI-MS): m/z calcd. for C14H21N2O5 [M+H]+: 297.1445, found: 297.1440.

(3-(3-aminophenoxy)propyl)carbamate tert-butyl (187)

The reaction was carried out as described in the general procedureN using nitro compound186 (239 mg, 0.81 mmol, 1.0 equiv.) and 10 wt% Pd/C (86 mg, 0.081 mmol, 0.1 equiv.) in MeOH (4.5 mL) for 3 h to provide compound187 (196 mg, 91%) as a yellow solid. Mp: 68 - 70 °C.<1>H NMR (250 MHz, CDCb) 87.05 (t, J = 8.0 Hz, 1H, CH), 6.37 - 6.27 (m, 2H, 2 x CH), 6.24 (t, J = 2.3 Hz, 1H, CH), 4.75 (brs, 1H, NH), 3.98 (t, J = 6.0 Hz, 2H, CH<2>), 3.65 (brs, 2H, NH<2>), 3.31 (q, J = 6.4 Hz, 2H, CH<2>), 1.95 (p, J = 6.3 Hz, 2H, CH<2>), 1.44 (s, 9H, 3 x CH<3>). HRMS (EI-MS) m/z calcd. for C<14>H<23>N<2>O<3>[M+H]<+>: 267.1703, found: 267.1702.

Example 97: (3-(3-(4-(5-methyl-7H-pyrrole[2,3-d]pyrimidin-4-yl)-1,2,3,6-tetrahydropyridin-1-carboxamido)phenoxy) Fert-butyl propyl)carbamate (188)

The reaction was carried out as described in the general procedure H with aniline 187 (78 mg, 0.29 mmol, 1.0 equiv.), 4-nitrophenyl chloroformate (71 mg, 0.35 mmol, 1.2 equiv.), DIPEA (122 pl, 0.70 mmol, 2.4 equiv.) and amine 4 (88 mg, 0.35 mmol, 1.2 equiv.) in dry THF (4.0 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM/MeOH from 98/2 to 95/5 to afford compound 188 (85 mg, 57%) as a white powder. Rf (DCM/MeOH 95/5) 0.42. Mp: degradation 103 °C<1>H NMR (250 MHz, DMSO-d<6>) 811.81 (s, 1H, NH), 8.64 (s, 1H, CH), 8.54 (s, 1H, NH), 7.35 - 7.27 (m, 1H, CH), 7.24 - 7.16 (m, 1H, CH), 7.17 - 7.02 (m, 2H, 2 x CH), 6.88 (t, J = 5.1 Hz, 1H, NH), 6.50 (dt, J = 7.6, 2.0 Hz, 1H, CH), 6.12 - 5.99 (m, 1H, CH), 4.21 (d, J= 2.6 Hz, 2H, CH<2>), 3.92 (t, J = 6.2 Hz, 2H, CH<2>), 3.73 (t, J = 5.6 Hz, 2H, CH<2>), 3.07 (q, J = 6.6 Hz, 2H, CH<2>), 2.68 (brs, 2H, CH<2>), 2.24 (s, 3H, CH<3>), 1.82 (p, J = 6.6 Hz, 2H, CH<2>), 1.37 (s, 9H, 3 x CH<3>). HRMS (EI-MS) m/z calcd. for C<27>H<35>N<6>O<4>[M+H]<+>: 507.2714, found: 507.2709.

1-((4,4-difluorocyclohexyl)methoxy)-3-nitrobenzene (189)

The reaction was carried out as described in the general procedure using 3-nitrophenol (300 mg, 2.16 mmol, 1.0 equiv.), (4,4-difluorocyclohexyl)methanol (562 pl, 4.32 mmol, 2.0 equiv.), PPh<3>(963 mg, 3.67 mmol, 1.7 equiv.) and DIAD (0.723 mL, 3.67 mmol, 1.7 equiv.) in dry THF (8 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of PE/DCM from 100 to 75/25 to provide compound 189 (524 mg, 89%) as a yellow solid. Rf (PE/DCM 80/20) 0.28. Mp: 75 - 77 °C.<1>H NMR (400 MHz, CDCb) 87.82 (dd, J = 8.1,2.0 Hz, 1H, CH), 7.71 (t, J = 2.3 Hz, 1H, CH), 7.43 (t, J = 8.2 Hz, 1H, CH), 7.21 (dd, J = 8.3, 2.5 Hz, 1H, CH), 3.89 (d, J= 6.0 Hz, 2H, CH<2>), 2.25-2.10 (m, 2H, CH<2>), 2.03 - 1.89 (m, 3H, CH CH<2>), 1.89 - 1.66 (m, 2H, CH<2>), 1.53 - 1.39 (m, 2H, CH<2>).<19>F NMR (376 MHz, CDCl<a>) 8 -91.6 (d, J = 236.5 Hz, 1F), -102.2 (dtt, J = 236.1, 33.5, 10.5 Hz, 1F). HRMS (EI-MS) No ionization by MH+ or MH- was detected.

3-((4,4-difluorocyclohexyl)methoxy)aniline (190)

The reaction was carried out as described in the general procedureN using nitro189 (308 mg, 1.14 mmol, 1.0 equiv.) and 10 wt% Pd/C (121 mg, 0.114 mmol, 0.1 equiv.) in MeOH (6 mL) for 3 h to provide compound190 (239 mg, 87%) as a colorless oil. The product was used in the next step without further purification.<1>H NMR (400 MHz, CDCb) 87.05 (t, J = 8.0 Hz, 1H, CH), 6.34 - 6.27 (m, 2H, 2 x CH), 6.23 (t, J = 2.3 Hz, 1H, CH), 3.77 (d, J = 6.3 Hz, 2H, CH<2>), 3.65 (s, 2H, NH<2>), 2.19 - 2.06 (m, 2H, CH<2>), 1.99 - 1.90 (m, 2H, CH<2>), 1.85 -1.65 (m, 3H, CH CH<2>), 1.49 - 1.34 (m, 2H, CH<2>).<19>F NMR (376 MHz, CDCb) 8 -91.4 (d, J = 235.7 Hz, 1F), -102.0 (dtt, J = 236.2, 33.2, 9.5 Hz, 1F). HRMS (EI-MS): m/z calcd. for C<13>H<18>F<2>NOT [M+H]<+>: 242.1351, found: 242.1350.

Example_____ 98 N-(3-((4,4-difluorocyclohexyl)methoxy)phenyl)-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridin- 1(2H)-carboxamide (191)

The reaction was carried out as described in the general procedure using aniline 190 (101 mg, 0.42 mmol, 1.0 equiv.), 4-nitrophenyl chloroformate (101 mg, 0.50 mmol, 1.2 equiv.), DIPEA (175 µl, 1.01 mmol, 2.4 equiv.) and amine 4 (126 mg, 0.50 mmol, 1.2 equiv.) in dry THF (6.0 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM/MeOH from 98/2 to 95/5 to afford compound 191 (119 mg, 59%) as a white powder. Rf (DCM/MeOH 95/5) 0.31. Mp: degradation 223 °C.<1>H NMR (400 MHz, DMSO-d<6>) 811.82 (s, 1H, NH), 8.65 (s, 1H, CH), 8.54 (s, 1H, NH), 7.31 (s, 1H, CH), 7.21 (s, 1H, CH), 7.17 - 7.05 (m, 2H, 2 x CH), 6.52 (d, J = 7.6 Hz, 1H, CH), 6.04 (brs, 1H, CH), 4.21 (d, J = 3.0 Hz, 2H,CH<2>), 3.80 (d, J = 5.8 Hz, 2H, CH<2>), 3.72 (t, J = 5.6 Hz, 2H, CH<2>), 2.67 (brs, 2H, CH<2>), 2.23 (s, 3H, CH<3>), 2.11 - 1.97 (m, 2H, CH<2>), 2.0 - 1.7 (m, 5H, 2 x CH<2>+ CH), 1.39 - 1.20 (m, 2H, CH<2>).<19>F NMR (376 MHz, DMSO) 8 -89.2 (d, J = 232.1 Hz, 1F), -99.6 (dt, J = 231.0, 35.9 Hz, 1F). HRMS (EI-MS) m/z calcd. for C<26>H<30>F<2>N<5>O [M+H]<+>: 482.2362, found: 482.2363.

4- ((3-nitrophenoxy)methyl)piperidine (192)

The reaction was carried out as described in the general procedure using 3-nitrophenol (700 mg, 5.03 mmol, 1.0 equiv.), 1-Boc-4-piperidinemethanol (2.17 g, 10.10 mmol, 2.0 equiv.), pH<3>(2.24 g, 8.55 mmol, 1.7 equiv.) and DIAD (1.68 mL, 8.55 mmol, 1.7 equiv.) in dry THF (28 mL). The reaction mixture was filtered over silica gel. The crude intermediate was then dissolved in dry DCM (30 mL), the reaction mixture was cooled to 0 °C and then 4 N HCl in 1,4-dioxane (6.0 mL, 24.10 mmol, 8.0 equiv.) was added. The solution was stirred at room temperature for 3 h and concentrated under reduced pressure. The white residue was partitioned between Et<2>O (20 mL) and H<2>O (20 mL), and the organic layer was removed. The aqueous phase was then washed with Et<2>O (15 mL), treated with saturated aqueous NaHCO<3>solution to pH 8-9, and extracted with DCM (3 x 40 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated under reduced pressure to afford compound 192 (326 mg, 27%) as a sticky orange solid which was used without further purification in the next step. 1H NMR (250 MHz, DMSO-d6) 87.80 (ddd, J = 8.1,2.2, 1.0 Hz, 1H, CH), 7.68 (t, J = 2.3 Hz, 1H, CH), 7.56 (t, J = 8.2 Hz, 1H, CH), 7.40 (ddd, J = 8.3, 2.5, 1.0 Hz, 1H, CH), 3.93 (d, J= 6.3 Hz, 2H, CH2), 2.99 (d, J = 12.2 Hz, 2H, CH2), 2.59 - 2.46 (m, 2H, CH2), 1.97 - 1.78 (m, 1H, CH), 1.72 (d, J = 12.8 Hz, 2H, CH2), 1.22 (qd, J = 12.1.4.1 Hz, 2H, CH2). HRMS (EI-MS) m/z calcd. for C12H17N2O3 [M+H]+: 237.1234, found: 237.1235.

1-methyl-4-((3-nitrophenoxy)methyl)piperidine (193)

To a microwave reaction vial charged with compound 192 (216 mg, 0.91 mmol, 1.0 equiv.) were added formic acid (0.8 mL) and formaldehyde solution (37 wt% in H2O, 0.48 mL, 6.40 mmol, 7.0 equiv.). The tube was sealed and subjected to microwave irradiation at 90 °C for 2 cycles of 10 min. The reaction mixture was then diluted in H2O (10 mL) and DCM (35 mL), and saturated aqueous NaHCO3 solution was added to pH ~ 9. The aqueous layer was extracted with DCM (3 x 20 mL), then the combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to afford compound193 (207 mg, 90%) as a yellow solid. The product was used without further purification in the next step. Mp: 68 - 70 °C. 1H NMR (250 MHz, DMSO-d6) 87.80 (ddd, J = 8.1, 2.2, 1.0 Hz, 1H, CH), 7.69 (t, J = 2.3 Hz, 1H, CH), 7.56 (t, J = 8.2 Hz, 1H, CH), 7.41 (ddd, J = 8.3, 2.5, 1.0 Hz, 1H, CH), 3.95 (d, J = 5.9 Hz, 2H, CH2), 2.88 - 2.70 (m, 2H, CH2), 2.15 (s, 3H, CH3), 1.92 - 1.79 (m, 2H, CH2), 1.78 - 1.61 (m, 3H, CH CH2), 1.42 - 1.15 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for C13H19N2O3 [M+H]+: 251.1390, found: 251.1387.

3-((1-methylpiperidin-4-yl)methoxy)aniline (194)

The reaction was carried out as described in the general procedureN using nitro193 (171 mg, 0.72 mmol, 1.0 equiv.) and 10 wt% Pd/C (77 mg, 0.07 mmol, 0.1 equiv.) in MeOH (4 mL) for 2 h to provide compound194 (131 mg, 82%) as a beige solid. The product was used without further purification in the next step. 1H NMR (250 MHz, DMSO-d6) 86.86 (t, J = 8.3 Hz, 1H, CH), 6.16 - 6.09 (m, 2H, 2 x CH), 6.05 (ddd, J= 8.1,2.3, 1.0 Hz, 1H, CH), 4.99 (s, 2H, NH2), 3.69 (d, J= 5.9 Hz, 2H, CH2), 2.81 - 2.70 (m, 2H, CH2), 2.14 (s, 3H, CH3), 1.83 (td, J = 11.6, 2.4 Hz, 2H, CH2), 1.77 - 1.54 (m, 3H, CH CH2), 1.37 - 1.15 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for C13H21N2 O[M+H]+: 221.1648, found: 221.1645.

Example 99: 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-W-(3-((1-methylpiperidin-4-yl)methoxy)phenyl)-3,6 -dihydropyridine-1(2H)-carboxamide (195)

The reaction was carried out as described in the general procedure using aniline 194 (113 mg, 0.51 mmol, 1.0 equiv.), 4-nitrophenyl chloroformate (124 mg, 0.62 mmol, 1.2 equiv.), DIPEA (322 pl, 3.60 mmol, 3.6 equiv.) and amine 4 (177 mg, 0.62 mmol, 1.2 equiv.) in dry THF (7.3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM/MeOH/NH 4 OH from 98/2/1 to 94/6/1 to provide compound 195 (80 mg, 34%) as a white solid.

Rf(DCM/MeOH/NH4OH 95/5/1) 0.27. Mp: degradation 135 °C. 1H NMR (250 MHz, DMSO-d6) 8 11.83 (s, 1H, NH), 8.64 (s, 1H, CH), 8.54 (s, 1H, NH), 7.32 (brs, 1H, CH), 7.20 (brs, 1H, CH), 7.16 - 7.02 (m, 2H, 2 x CH), 6.51 (d, J = 7.4 Hz, 1H, CH), 6.04 (s, 1H, CH), 4.21 (brs, 2H, CH2), 3.87 - 3.66 (m, 4H, 2 x CH2), 2.83 (d, J = 11.0 Hz, 2H, CH2), 2.67 (brs, 2H, CH2), 2.23 (s, 3H, CH3), 2.20 (s, 3H, CH3), 1.96 (t, J = 11.5 Hz, 2H, CH2), 1.82 - 1.62 (m, 3H, CH2 CH), I, 41 - 1.19 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for C26H33N6O2 [M+H]+: 461.2660, found: 461.2663.

Example 100: N-methyl-4-(4-(4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,2,3,6-tetrahydropyridine-1-carboxamido )phenoxy)picolinamide (196)

The reaction was carried out as described in the general procedure using 4-(4-aminophenoxy)-N-methylpicolinamide (100 mg, 0.41 mmol, 1.0 equiv.), 4-nitrophenyl chloroformate (99 mg, 0.49 mmol, 1.2 equiv.), DIPEA (258 pl, 1.48 mmol, 3.6 equiv.) and amine4(142 mg, 0.49 mmol, 1.2 equiv.) in dry THF (6 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM/MeOH/NH4OH from 98/2/0.1 to 93/7/0.1 to provide compound196 (175 mg, 88%) as a beige solid. Rf (DCM/MeOH/NH4OH 95/5/0.1) 0.44. Mp: degradation 149 °C. 1H NMR (250 MHz, CDCb) 8 I I , 83 (s, 1H, NH), 8.80 - 8.71 (m, 2H, 2 x NH), 8.65 (s, 1H, CH), 8.52 - 8.48 (m, 1H, CH), 7.70 - 7.60 (m, 2H, 2 x CH), 7.38 (d, J = 2.8 Hz, 1H, CH), 7.35 - 7.29 (m, 1H, CH), 7.17 - 7.08 (m, 3H, 3 x CH), 6.06 (brs, 1H, CH), 4.30 - 4.21 (m, 2H, CH2), 3.76 (t, J = 5.5 Hz, 2H, CH2), 2.79 (d, J = 4.8 Hz, 3H, CH3), 2.70 (brs, 2H, CH2), 2.29 - 2.22 (m, 3H, CH3). HRMS (EI-MS) m/z calcd. for C26H26N7O3 [M+H]+: 484.2092, found: 484.2086.

4-(3-aminophenoxy)-N-methyl-2-pyridinecarboxamide (197)

To a solution of 3-aminophenol (336 mg, 3.08 mmol, 1.05 equiv.) in dry DMSO (2 mL) under argon was added t-BuOK (361 mg, 3.22 mmol, 1.1 equiv.). The solution was stirred at room temperature for 30 min, then 4-chloro-N-methylpicolinamide (500 mg, 2.93 mmol, 1.0 equiv.) was added. The reaction mixture was stirred at 80 °C for 3 h, then cooled to room temperature, then diluted with H2O (40 mL) and EtOAc (50 mL). The aqueous phase was separated and extracted with EtOAc (2 x 30 mL), then the combined organic layers were washed with brine (15 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM/MeOH from 100 to 98/2 to provide compound 197 (516 mg, 72%) as a colorless oil.

Rf(DCM/MeOH 98/2) 0.59. 1H NMR (250 MHz, DMSO-d6) 88.75 (q, J = 4.8 Hz, 1H, NH), 8.49 (dd, J = 5.6, 0.5 Hz, 1H, CH), 7.41 (d, J = 2.6 Hz, 1H, CH), 7.20 - 7.02 (m, 2H, 2 x CH), 6.51 (ddd, J = 8.1, 2.1, 0.9 Hz, 1H, CH), 6.32 (t, J = 2.2 Hz, 1H, CH), 6.27 (ddd, J = 7.9, 2.4, 0.9 Hz, 1H, CH), 5.39 (s, 2H, NH2), 2.79 (d, J= 4.9 Hz, 3H, CH3). HRMS (EI-MS) m/z calcd. for C13H14N3O2 [M+H]+: 244.1081, found: 244.1080.

Example 101: W-methyl-4-(3-(4-(5-methyl-7H-pyrrolo[2,3-d]pinmidin-4-yl)-1,2,3,6-tetrahydropyridine-1-carboxamido )phenoxy)picolinamide (198)

The reaction was carried out as described in the general procedure H with aniline 197 (110 mg, 0.45 mmol, 1.0 equiv.), 4-nitrophenyl chloroformate (109 mg, 0.54 mmol, 1.2 equiv.), DIPEA (284 pl, 1.63 mmol, 3.6 equiv.) and amine 4 (156 mg, 0.54 mmol, 1.2 equiv.) in dry THF (7 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM/MeOH from 98/2 to 95/5 to provide compound 198 (160 mg, 73%) as a beige powder. Rf (DCM/MeOH 95/5) 0.54. Mp: 211 - 213 °C. 1H NMR (250 MHz, DMSO-d6) 811.82 (s, 1H, NH), 8.85 - 8.71 (m, 2H, 2 x NH), 8.64 (s, 1H, CH), 8.52 (d, J = 5.6 Hz, 1H, CH), 7.52 - 7.33 (m, 4H, 4 x CH), 7.30 (brs, 1H, CH), 7.18 (dd, J = 5.6, 2.6 Hz, 1H, CH), 6.80 (ddd, J = 7.8, 2.3, 1.3 Hz, 1H, CH), 6.03 (brs, 1H, CH), 4.21 (d, J= 3.1 Hz, 2H, CH2), 3.73 (t, J = 5.6 Hz, 2H, CH2), 2.79 (d, J = 4.8 Hz, 3H, CH3), 2.72 - 2.67 (m, 2H, CH2), 2.22 (d, J = 1.0 Hz, 3H, CH3). HRMS (EI-MS) m/z calcd. for C26H26N7O3 [M+H]+: 484.2092, found: 484.2088.

3-(3-fluorophenoxy)aniline (199)

The reaction was carried out as described in the general procedure using 3-fluoroiodobenzene (235 µl, 2.00 mmol, 1.0 equiv.), 3-aminophenol (262 mg, 2.40 mmol, 1.2 equiv.), copper(I) iodide (19 mg, 0.10 mmol, 5 mol %), 2-picolinic acid (25 mg, 0.20 mmol, 10 mol %) and K3PO4 (849 mg, 4.00 mmol, 2.0 equiv.) in dry DMSO (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of PE/EtOAc from 90/10 to 80/20 to afford compound199 (406 mg, quantitative) as an orange liquid. Rf (PE/EtOAc 80/20) 0.35. 1H r Mn (400 MHz, CDCb) 87.33 - 7.22 (m, 1H, CH), 7.14 (t, J = 8.0 Hz, 1H, CH), 6.85 - 6.70 (m, 3H, 3 x CH), 6.46 (ddd, J = 19.6, 8.1, 2.2 Hz, 2H, 2 x CH), 6.38 (t, J = 2.3 Hz, 1H, CH), 3.74 (brs, 2H, NH2). 19F NMR (376 MHz, CDCb) 8 -111.2. HRMS (EI-MS): m/z calcd. for C12H11FNO [M+H]+: 204.0819, found: 204.0824.

Example___________102: W-(3-((3-fluorophenoxy)phenyl)-4-(5-methyl-7H-pyrrolo[2,3-d]pmmidin-4-yl)-3,6-dihydropindin-1(2H) -carboxamide (200)

The reaction was carried out as described in the general procedure using aniline 199 (77 mg, 0.38 mmol, 1.0 equiv.), 4-nitrophenyl chloroformate (91 mg, 0.45 mmol, 1.2 equiv.), DIPEA (237 pl, 1.36 mmol, 2.4 equiv.) and amine 4 (130 mg, 0.45 mmol, 1.2 equiv.) in dry THF (5.4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM/MeOH from 98/2 to 97/3 to afford compound 200 (129 mg, 76%) as a brown solid. Rf (DCM/MeOH 95/5) 0.33. Mp: degradation 150 °C. 1H NMR (400 MHz, DMSO-d6) 811.83 (s, 1H, NH), 8.70 (s, 1H, NH), 8.64 (s, 1H, CH), 7.47 - 7.38 (m, 1H, CH), 7.38 - 7.23 (m, 4H, 4 x CH), 6.96 (td, J = 8.5, 2.5 Hz, 1H, CH), 6.90 - 6.80 (m, 2H, 2 x CH), 6.67 (d, J= 8.0 Hz, 1H, CH), 6.03 (brs, 1H, CH), 4.20 (d, J= 3.0 Hz, 2H, CH2), 3.71 (t, J = 5.5 Hz, 2H, CH2), 2.66 (brs, 2H, CH2), 2.22 (s, 3H, CH3). 19F NMR (376 MHz, DMSO-d6) 8 -111.0 (s, 1F). HRMS (EI-MS) m/z calcd. for C25H23 FN5O2 [M+H]+: 444.1830, found: 444.1835.

3-(4-fluorophenoxy)aniline (201)

The reaction was carried out as described in the general procedure using 4-fluoroiodobenzene (231 µl, 2.00 mmol, 1.0 equiv.), 3-aminophenol (262 mg, 2.40 mmol, 1.2 equiv.), copper(I) iodide (19 mg, 0.10 mmol, 5 mol %), 2-picolinic acid (25 mg, 0.20 mmol, 10 mol %) and K3PO4 (849 mg, 4.00 mmol, 2.0 equiv.) and dry DMSO (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of PE/EtOAc from 100 to 90/10 to afford compound201 (332 mg, 82%) as an orange oil. Rf (PE/EtOAc 90/10) 0.32. 1H NMR (250 MHz, CDCb) 87.12 - 6.94 (m, 5H, 5 x CH), 6.41 (ddd, J = 8.0, 2.2, 0.9 Hz, 1H, CH), 6.34 (ddd, J = 8.1, 2.3, 0.9 Hz, 1H, CH), 6.28 (td, J = 2.3, 0.4 Hz, 1H, CH), 3.69 (brs, 2H, NH2). HRMS (EI-MS): m/z calcd. for C12H11FNO [M+H]+: 204.0819, found: 204.0823.

All spectral data corresponded to the bibliographic values found in Maiti D., Buchwald S. L., J. Am. Chem. Soc. 2009, 131, 17423-17429.

Example__________ 103: N-(3-(4-fluorophenoxy)phenyl)-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1 (2H) -carboxamide (202)

The reaction was carried out as described in the general procedure using aniline 201 (79 mg, 0.39 mmol, 1.0 equiv.), 4-nitrophenyl chloroformate (94 mg, 0.47 mmol, 1.2 equiv.), DIPEA (244 pl, 1.40 mmol, 2.4 equiv.) and amine 4 (134 mg, 0.47 mmol, 1.2 equiv.) in dry THF (5.6 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM/MeOH from 98/2 to 97/3 to afford compound 202 (129 mg, 74%) as a white powder. Rf (DCM/MeOH 95/5) 0.25. Mp: 213 - 215 °C. 1H NMR (400 MHz, DMSO-d6) 811.82 (s, 1H, NH), 8.65 (s, 1H, NH), 8.64 (s, 1H, CH), 7.34 -7.28 (m, 2H, 2 x CH), 7.27 - 7.19 (m, 4H, 4 x CH), 7.12 - 7.00 (m, 2H, 2 x CH), 6.59 (dd,J =7.6, 2.3 Hz, 1H, CH), 6.03 (brs, 1H, CH), 4.26 - 4.15 (m, 2H, CH2), 3.71 (t, J = 5.6 Hz, 2H, CH2), 2.66 (brs, 2H, CH2), 2.22 (s, 3H, CH3). 19F NMR (376 MHz, DMSO--d6) 8 -119.99 - 120.08 (m, 1F). HRMS (EI-MS) m/z calcd. for C25H23 FN5O2 [M+H]+: 444.1830, found: 444.1836.

3-(3-chlorophenoxy)aniline (203)

The reaction was carried out as described in the general procedure using 3-chloroiodobenzene (248 µl, 2.00 mmol, 1.0 equiv.), 3-aminophenol (262 mg, 2.40 mmol, 1.2 equiv.), copper(I) iodide (19 mg, 0.10 mmol, 5 mol %), 2-picolinic acid (25 mg, 0.20 mmol, 10 mol %) and K3PO4 (849 mg, 4.00 mmol, 2.0 equiv.) in dry DMSO (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of PE/EtOAc from 95/5 to 80/20 to afford compound203 (427 mg, 97%) as an orange liquid. Rf (PE/EtOAc 80/20) 0.39. 1H NMR (250 MHz, CDCb) 87.23 (t, J = 8.1 Hz, 1H, CH), 7.12 (t, J = 8.0 Hz, 1H, CH), 7.05 (ddd, J = 7.9, 2.0, 1.0 Hz, 1H, CH), 6.99 (t, J = 2.1 Hz, 1H, CH), 6.90 (ddd, J = 8.2, 2.4, 1.0 Hz, 1H, CH), 6.46 (ddd, J = 8.0, 2.2, 0.9 Hz, 1H, CH), 6.40 (ddd, J = 8.0, 2.3, 0.9 Hz, 1H, CH), 6.34 (t, J = 2.2 Hz, 1H, CH), 3.72 (brs, 2H, NH2). HRMS (EI-MS): m/z calcd. for C^HuClNO [M+H]+: 220.0524, found: 220.0525.

Example 104: W-(3-(3-chlorophenoxy)phenyl)-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H) -carboxamide (204)

The reaction was carried out as described in the general procedure using aniline 203 (90 mg, 0.41 mmol, 1.0 equiv.), 4-nitrophenyl chloroformate (99 mg, 0.49 mmol, 1.2 equiv.), DIPEA (258 pl, 1.48 mmol, 2.4 equiv.) and amine 4 (141 mg, 0.49 mmol, 1.2 equiv.) in dry THF (5.9 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM/MeOH from 98/2 to 95/5 to afford compound 204 (161 mg, 85%) as a white solid. Rf (DCM/MeOH 95/5) 0.39. Mp: degradation 124 °C. 1H NMR (400 MHz, DMSO-d6) 811.82 (s, 1H, NH), 8.70 (s, 1H, NH), 8.64 (s, 1H, CH), 7.45 - 7.25 (m, 5H, 5 x CH), 7.22 - 7.16 (m, 1H, CH), 7.08 - 7.05 (m, 1H, CH), 6.98 (dd, J = 8.3, 2.4 Hz, 1H, CH), 6.66 (d, J = 8.0 Hz, 1H, CH), 6.09 - 5.99 (m, 1H, CH), 4.20 (d, J = 3.1 Hz, 2H, CH2), 3.72 (t, J = 5.6 Hz, 2H, CH2), 2.67 (brs, 2H, CH2), 2.22 (s, 3H, CH3). HRMS (EI-MS) m/z calcd. for C25H23ClN5O2 [M+H]+: 460.1535, found: 460.1539.

3-(4-bromo-2-chlorophenoxy)aniline (205)

To a solution of 3-aminophenol (274 mg, 2.51 mmol, 1.05 equiv.) in dry DMSO (2 mL) under argon was added t-BuOK (295 mg, 2.63 mmol, 1.1 equiv.). The solution was stirred at room temperature for 30 min and then 4-bromo-2-chloro-1-fluorobenzene (290 mL, 2.39 mmol, 1.0 equiv.) was added. The reaction mixture was stirred at 80 °C for 18 h, then cooled to room temperature, diluted with H2O (25 mL) and EtOAc (50 mL). The aqueous phase was separated and extracted with EtOAc (2 x 50 mL), then the combined organic layers were washed with brine (3 x 20 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of PE/EtOAc from 100 to 90/10 to afford compound 205 (612 mg, 86%) as an orange oil. Rf (PE/EtOAc 90/10) 0.21. 1H NMR (250 MHz, CDCb) 87.59 (d, J = 2.4 Hz, 1H, CH), 7.31 (dd, J = 8.7, 2.4 Hz, 1H, CH), 7.10 (t, J = 8.0 Hz, 1H, CH), 6.87 (d, J = 8.7 Hz, 1H, CH), 6.44 (ddd, J = 8.0, 2.2, 0.9 Hz, 1H, CH), 6.33 (ddd, J = 8.0, 2.4, 0.9 Hz, 1H, CH), 6.28 (t, J = 2.2 Hz, 1H, CH), 3.72 (brs, 2H, NH2). HRMS (EI-MS): m/z calcd. for C12H10BrClNO [M+H]+: 299.9607, found: 299.9606.

Example 105: N-(3-(4-bromo-2-chlorophenoxy)phenyl)-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridin- 1(2H)-carboxamide (206)

The reaction was carried out as described in the general procedure using aniline 205 (65 mg, 0.22 mmol, 1.0 equiv.), 4-nitrophenyl chloroformate (53 mg, 0.26 mmol, 1.2 equiv.), DIPEA (137 µl, 0.79 mmol, 2.4 equiv.) and amine 4 (75 mg, 0.26 mmol, 1.2 equiv.) in dry THF (3.0 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM/MeOH from 98/2 to 96/4 to afford compound 206 (87 mg, 73%) as a white solid. Rf (DCM/MeOH 95/5) 0.30. Mp: degradation 148 °C. 1H NMR (250 MHz, DMSO-d6) 811.85 (s, 1H, NH), 8.70 (s, 1H, NH), 8.64 (s, 1H, CH), 7.89 (d, J = 2.4 Hz, 1H, CH), 7.57 (dd, J = 8.7, 2.4 Hz, 1H, CH), 7.40 - 7.19 (m, 4H, 4 x CH), 7.06 (d, J = 8.8 Hz, 1H, CH), 6.61 (ddd, J = 7.8, 2.5, 1.2 Hz, 1H, CH), 6.03 (brs, 1H, CH), 4.19 (d, J = 3.1 Hz, 2H, CH2), 3.70 (t, J = 5.6 Hz, 2H, CH2), 2.66 (brs, 2H, CH2), 2.22 (d, J = 1.1 Hz, 3H, CH3). HRMS (EI-MS) m/z calcd. for C25H22BrClN5O2 [M+H]+: 540.0620, found: 540.0621.

3-(pyridin-3-yloxy)aniline (207)

The reaction was carried out as described in the general procedureUsing 3-iodopyridine (410 mg, 2.00 mmol, 1.0 equiv.), 3-aminophenol (262 mg, 2.40 mmol, 1.2 equiv.), copper(I) iodide (19 mg, 0.10 mmol, 5 mol%), 2-picolinic acid (25 mg, 0.20 mmol, 10 mol%) and K3PO4 (849 mg, 4.00 mmol, 2.0 equiv.) in dry DMSO (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of PE/EtOAc from 80/20 to 50/50 to provide compound 207 (247 mg, 55%) as a brown oil. Rf(PE/EtOAc 50/50) 0.30. 1H NMR (250 MHz, CDCb) 88.41 (dd, J= 2.8, 0.8 Hz, 1H, CH), 8.35 (dd, J= 4.5, 1.6 Hz, 1H, CH), 7.34 - 7.21 (m, 2H, 2 x CH), 7.12 (t, J = 8.0 Hz, 1H, CH), 6.46 (ddd, J = 8.0, 2.2, 0.9 Hz, 1H, CH), 6.39 (ddd, J = 8.0, 2.3, 0.9 Hz, 1H, CH), 6.34 (t, J = 2.2 Hz, 1H, CH), 3.73 (brs, 2H, NH2). HRMS (EI-MS) m/z calcd. for C11H11N2 O[M+H]+: 187.0866, found: 187.0871.

All spectral data corresponded to the bibliographic values found in Maiti D., Buchwald S. L., J. Am. Chem. Soc. 2009, 131, 17423-17429.

Example 106: 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-W-(3-(pyridin-3-yloxy)phenyl)-3,6-dihydropyridin-1( 2H)-carboxamide (208)

The reaction was carried out as described in the general procedure using aniline 207 (70 mg, 0.38 mmol, 1.0 equiv.), 4-nitrophenyl chloroformate (91 mg, 0.45 mmol, 1.2 equiv.), DIPEA (236 pl, 1.35 mmol, 2.4 equiv.) and amine 4 (130 mg, 0.45 mmol, 1.2 equiv.) in dry THF (5.4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM/MeOH from 98/2 to 95/5 to afford compound 208 (112 mg, 68%) as a white powder. Rf (DCM/MeOH 95/5) 0.24. Mp: degradation 132 °C. 1H NMR (250 MHz, DMSO-d6) 811.83 (s, 1H, NH), 8.71 (s, 1H, NH), 8.64 (s, 1H, CH), 8.43 - 8.32 (m, 2H, 2 x CH), 7.49 - 7.40 (m, 2H, 2 x CH), 7.38 - 7.24 (m, 4H, 4 x CH), 6.72 - 6.61 (m, 1H, CH), 6.03 (brs, 1H, CH), 4.19 (d, J = 2.4 Hz, 2H, CH2), 3.71 (t, J = 5.5 Hz, 2H, CH2), 2.66 (brs, 2H, CH2), 2.22 (s, 3H, CH3). HRMS (EI-MS) m/z calcd. for C24H23N6O2 [M+H]+: 427.1877, found: 427.1885.

1-(benzyloxy)-3-iodobenzene (209)

To a solution of 3-iodophenol (500 mg, 2.27 mmol, 1.0 equiv.) in acetone (3 mL) was added K2CO3 (471 mg, 3.41 mmol, 1.5 equiv.) and benzyl bromide (406 µl, 3.41 mmol, 1.5 equiv.). The resulting suspension was stirred at room temperature for 18 h, diluted with saturated NH4Cl solution (15 mL), then the aqueous layer was separated and extracted with Et2O (2 x 30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was precipitated from PE at 0 °C, after filtration of the solid, the filtrate was evaporated and precipitated again to give compound 209 (366 mg, 52%) as a white powder. 1H NMR (250 MHz, CDCb) 87.48 - 7.27 (m, 7H, 7 x CH), 7.05 - 6.89 (m, 2H, CH), 5.03 (s, 2H, CH2).

All spectral data corresponded to the literature values found by Kutz S. K. et al., Synthesis, 2017, 49, 275-292.

3-(3-(benzyloxy)phenoxy)aniline (210)

The reaction was carried out as described in the general procedure by adding iodoaryl ester209 (310 mg, 1.00 mmol, 1.0 equiv.), 3-aminophenol (131 mg, 1.20 mmol, 1.2 equiv.), copper(I) iodide (10 mg, 0.05 mmol, 5 mol %), 2-picolinic acid (12 mg, 0.10 mmol, 10 mol %) and K3PO4 (425 mg, 2.00 mmol, 2.0 equiv.) in dry DMSO (2 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of PE/EtOAc from 90/10 to 80/20 to afford compound210 (221 mg, 76%) as a brown oil. Rf (PE/EtOAc 80/20) 0.38. 1H NMR (250 MHz, CDCb) 87.46 - 7.30 (m, 5H, 5 x CH), 7.22 (t, J = 8.1 Hz, 1H, CH), 7.09 (t, J = 8.0 Hz, 1H, CH), 6.72 (dd, J = 8.2, 2.4 Hz, 1H, CH), 6.68 - 6.58 (m, 2H, 2 x CH), 6.48 - 6.37 (m, 2H, 2 x CH), 6.33 (t, J = 2.2 Hz, 1H, CH), 5.02 (s, 2H, CH2), 3.68 (s, 2H, NH2). HRMS (EI-MS) m/z calcd. for C19H18NO2 [M+H]+: 292.1332, found: 292.1336.

Example________ 107: W-(3-(3-(benzyloxy)phenoxy)phenyl)-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridin-1 (2H)-carboxamide (211)

The reaction was carried out as described in the general procedure using aniline 210 (54 mg, 0.19 mmol, 1.0 equiv.), 4-nitrophenyl chloroformate (45 mg, 0.22 mmol, 1.2 equiv.), DIPEA (116 pl, 0.67 mmol, 2.4 equiv.) and amine 4 (64 mg, 0.22 mmol, 1.2 equiv.) in dry THF (2.6 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM/MeOH from 100 to 97/3 to afford compound 211 (79 mg, 79%) as a white powder. Rf (DCM/MeOH 95/5) 0.29. Mp: degradation 110 °C. 1H NMR (250 MHz, DMSO-d6) 811.82 (s, 1H, NH), 8.67 (brs, 1H, NH), 8.64 (s, 1H, CH), 7.48 -7.19 (m, 10H, 10 x CH), 6.78 (ddd, J = 8.3, 2.5, 0.9 Hz, 1H, CH), 6.66 (t, J = 2.3 Hz, 1H, CH), 6.64 - 6.53 (m, 2H, 2 x CH), 6.05 - 5.99 (m, 1H, CH), 5.08 (s, 2H, CH2), 4.26 - 4.14 (m, 2H, CH2), 3.71 (t, J = 5.5Hz, 2H, CH2), 2.66 (brs, 2H, CH2), 2.22 (d, J= 1.0 Hz, 3H, CH3). HRMS (EI-MS) m/z calcd. for C32H30N5O3 [M+H]+: 532.2343, found: 532.2351.

3-(3-aminophenoxy)phenol (212)

The reaction was carried out as described in the general procedureN using compound210 (139 mg, 0.48 mmol, 1.0 equiv.) and 10 wt% Pd/C (51 mg, 0.05 mmol, 0.1 equiv.) in MeOH (2.7 mL) for 3 h to provide compound212 (90 mg, 94%) as an amorphous beige solid. 1H NMR (250 MHz, DMSO-d6) 8 9.51 (s, 1H, OH), 7.12 (t, J = 8.1 Hz, 1H, CH), 6.98 (t, J = 8.0 Hz, 1H, CH), 6.48 (ddd, J = 8.1, 2.3, 1.0 Hz, 1H, CH), 6.39 (ddd, J = 8.1, 2.4, 1.0 Hz, 1H, CH), 6.35 - 6.27 (m, 2H, 2 x CH), 6.17 (t, J = 2.2 Hz, 1H, CH), 6.12 (ddd, J = 7.9, 2.4, 1.0 Hz, 1H, CH), 5.20 (brs, 2H, NH2). HRMS (EI-MS) m/z calcd. for C12H12NO2 [M+H]+: 202.0863, found: 202.0867.

Example__________ 108: W-(3-((3-hydroxyphenoxy)phenyl)-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridin-1(2H )-carboxamide (213)

The reaction was carried out as described in the general procedure using aniline 212 (79 mg, 0.39 mmol, 1.0 equiv.), 4-nitrophenyl chloroformate (95 mg, 0.47 mmol, 1.2 equiv.), DIPEA (246 pl, 1.41 mmol, 2.4 equiv.) and amine 4 (136 mg, 0.47 mmol, 1.2 equiv.) in dry THF (5.6 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM/MeOH from 98/2 to 96/4 to afford compound 213 (80 mg, 46%) as a white powder. Rf (DCM/MeOH 95/5) 0.22. Mp: degradation 144 °C. 1H NMR (250 MHz, DMSO-d6) 811.81 (s, 1H, NH), 9.55 (s, 1H, OH), 8.65 (s, 1H, NH), 8.64 (s, 1H, CH), 7.37 - 7.20 (m, 4H, 4 x CH), 7.15 (t, J = 8.1 Hz, 1H, CH), 6.61 (ddd, J = 7.7, 2.4, 1.3 Hz, 1H, CH), 6.52 (ddd, J = 8.1, 2.3, 0.9 Hz, 1H, CH), 6.43 (ddd, J = 8.1, 2.4, 0.9 Hz, 1H, CH), 6.38 (t, J = 2.3Hz, 1H, CH), 6.08 -5.98 (m, 1H, CH), 4.20 (d, J = 3.1 Hz, 2H, CH2), 3.71 (t, J = 5.5 Hz, 2H, CH2), 2.66 (brs, 2H, CH2), 2.22 (d, J = 1.1 Hz, 3H, CH3). HRMS (EI-MS) m/z calcd. for C25H24N5O3 [M+H]+: 442.1874, found: 442.1883.

3-Iodophenyl dimethylcarbamate (214)

To a solution of 3-iodophenol (600 mg, 2.73 mmol, 1.0 equiv.) in dry MeCN (14 mL) under argon was added K2CO3 (567 mg, 4.10 mmol, 1.5 equiv.) and dimethylcarbamyl chloride (377 µl, 4.10 mmol, 1.5 equiv.). The reaction mixture was stirred at reflux for 18 h, then cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and H2O (20 mL), then the aqueous layer was separated and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with 1 M KOH (15 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of PE/EtOAc from 100 to 90/10 to afford compound 214 (730 mg, 92%) as a colorless oil. Rf (PE/EtOAc 90/10) 0.40. 1H NMR (250 MHz, CDCb) 8 7.57 - 7.47 (m, 2H, 2 x CH), 7.14 - 7.01 (m, 2H, 2 x CH), 3.04 (d, J = 18.5 Hz, 6H, 2 x CH3). HRMS (EI-MS) m/z calcd. for C9H11INO2 [M+H]+: 291.9829, found: 291.9834.

3-(3-aminophenoxy)phenyl dimethylcarbamate (215)

The reaction was carried out as described in the general procedure by combining iodoaryl ether214(582 mg, 2.00 mmol, 1.0 equiv.), 3-aminophenol (262 mg, 2.40 mmol, 1.2 equiv.), copper(I) iodide (19 mg, 0.10 mmol, 5 mol%), 2-picolinic acid (25 mg, 0.20 mmol, 10 mol%) and K3PO4 (849 mg, 4.00 mmol, 2.0 equiv.) in dry DMSO (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of PE/EtOAc from 80/20 to 70/30 to afford compound215(166 mg, 30%) as a brown oil. Rf (PE/EtOAc 70/30) 0.18. 1H NMR (250 MHz, CDCb) 8 7.28 (t, J = 8.2 Hz, 1H, CH), 7.10 (t, J = 8.0 Hz, 1H, CH), 6.85 (dd, J = 8.2, 2.3 Hz, 2H, 2 x CH), 6.76 (t, J = 2.3 Hz, 1H, CH), 6.43 (ddd, J = 8.0, 2.2, 1.2 Hz, 2H, 2 x CH), 6.35 (t, J = 2.2 Hz, 1H, CH), 3.69 (s, 2H, NH2), 3.03 (d, J = 19.1 Hz, 6H, 2 x CH3). HRMS (EI-MS) m/z calcd. for C15H17N2O3 [M+H]+: 273.1234, found: 273.1235.

Example 109: 3-(3-(4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,2,3,6-tetrahydropyridin-1-carboxamido)phenoxy)dimethylcarbamate phenyl (216)

The reaction was carried out as described in the general procedure using aniline 215 (69 mg, 0.25 mmol, 1.0 equiv.), 4-nitrophenyl chloroformate (61 mg, 0.30 mmol, 1.2 equiv.), DIPEA (157 pl, 0.91 mmol, 2.4 equiv.) and amine 4 (87 mg, 0.30 mmol, 1.2 equiv.) in dry THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM/MeOH from 98/2 to 95/5 to afford compound 216 (81 mg, 64%) as a white powder after coevaporation with ethanol. Rf (DCM/MeOH 95/5) 0.27. Mp: degradation 132 °C. 1H NMR (250 MHz, DMSO-d6) 811.84 (s, 1H, NH), 8.72 (s, 1H, NH), 8.64 (s, 1H, CH), 7.45 - 7.19 (m, 5H, 5 x CH), 6.94 - 6.81 (m, 2H, 2 x CH), 6.74 (t, J = 2.3 Hz, 1H, CH), 6.64 (ddd, J = 7.8, 2.4, 1.2 Hz, 1H, CH), 6.12 - 5.97 (m, 1H, CH), 4.28 - 4.13 (m, 2H, CH2), 3.72 (t, J = 5.6 Hz, 2H, CH2), 3.00 (s, 3H, CH3), 2.88 (s, 3H, CH3), 2.67 (brs, 2H, CH2), 2.22 (s, 3H, CH3). HRMS (EI-MS) m/z calcd. for C28H29N6O4 [M+H]+: 513.2245, found: 513.2235.

N-(3-iodophenyl)acetamide (217)

A solution of 3-iodoaniline (329 µl, 2.74 mmol, 1.0 equiv.) in acetic anhydride (5.5 mL) was stirred at room temperature for 4 h. The reaction mixture was poured into cold water, neutralized with 1 M KOH and extracted with DCM (4 × 50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to afford compound217 (714 mg, quantitative) as a brown solid. The product obtained was used in the next step without further purification. 1H r Mn (250 MHz, CDCb) 87.90 (s, 1H, CH), 7.45 (t, J = 8.9 Hz, 2H, 2 x CH), 7.27 (brs, 1H, NH), 7.03 (t, J= 8.0 Hz, 1H, CH), 2.17 (s, 3H, CH3).

All spectral data corresponded to literature values as found in Linstad E. J. et al., Org. Biomol. Chem., 2017, 15, 2246–2252.

N-(3-(3-aminophenoxy)phenyl)acetamide (218)

The reaction was carried out as described in the general procedure. Using iodoaryl ester217 (522 mg, 2.00 mmol, 1.0 equiv.), 3-aminophenol (262 mg, 2.40 mmol, 1.2 equiv.), copper(I) iodide (19 mg, 0.10 mmol, 5 mol%), 2-picolinic acid (25 mg, 0.20 mmol, 10 mol%) and K3PO4 (849 mg, 4.00 mmol, 2.0 equiv.) in dry DMSO (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of PE/EtOAc from 80/20 to 50/50 to provide compound 218 (320 mg, 66%) as a brown oil. Rf(PE/EtOAc 50/50) 0.16. 1H NMR (250 MHz, DMSO-d6) 89.98 (s, 1H, NH), 7.36 - 7.19 (m, 3H, 3 x CH), 6.99 (t, J = 8.0 Hz, 1H, CH), 6.65 (ddd, J = 7.4, 2.3, 1.6 Hz, 1H, CH), 6.31 (ddd, J = 8.0, 2.1, 1.0 Hz, 1H, CH), 6.22 - 6.08 (m, 2H, 2 x CH), 5.24 (s, 2H, NH2), 2.00 (s, 3H, CH3), HRMS (EI-MS) m/z calcd. for C14H15N2O2 [M+H]+: 243.1128, found: 243.1134.

Example_______110: W-(3-((3-acetamidophenoxy)phenyl)-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridin-1(2H) -carboxamide (219)

The reaction was carried out as described in the general procedure using aniline 218 (100 mg, 0.41 mmol, 1.0 equiv.), 4-nitrophenyl chloroformate (100 mg, 0.50 mmol, 1.2 equiv.), DIPEA (260 µl, 1.49 mmol, 2.4 equiv.) and amine 4 (143 mg, 0.50 mmol, 1.2 equiv.) in dry THF (6.0 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM/MeOH from 98/2 to 94/6 to afford compound 219 (46 mg, 24%) as a white powder after coevaporation with ethanol. Rf (DCM/MeOH 95/5) 0.30. Mp: degradation 156 °C. 1H NMR (250 MHz, DMSO-d6) 8 11.84 (s, 1H, NH), 10.00 (s, 1H, NH), 8.68 (s, 1H, NH), 8.64 (s, 1H, CH), 7.50 - 7.17 (m, 7H, 7 x CH), 6.77 - 6.56 (m, 2H, 2 x CH), 6.03 (brs, 1H, CH), 4.20 (s, 2H, CH2), 3.71 (t, J = 5.6 Hz, 2H, CH2), 2.66 (brs, 2H, CH2), 2.22 (s, 3H, CH3), 2.01 (s, 3H, CH3). HRMS (EI-MS) m/z calcd. for C27H27N6O3 [M+H]+: 483.2139, found: 483.2135.

3-iodo-N-methylbenzamide (220)

Under argon atmosphere, 3-iodobenzoic acid (400 mg, 1.61 mmol, 1.0 equiv.), DMAP (236 mg, 1.93 mmol, 1.2 equiv.) and HATU (734 mg, 1.93 mmol, 1.2 equiv.) were suspended in dry THF (16 mL) followed by the addition of DIPEA (336 mL, 1.93 mmol, 1.2 equiv.). The resulting suspension was stirred at room temperature for 20 min, then methylamine hydrochloride (130 mg, 1.93 mmol, 1.2 equiv.) was added and the reaction mixture was stirred at room temperature for 30 min and concentrated to dryness. The residue was dissolved in DCM (50 mL), the organic layer was washed with 1 M HCl (15 mL), H2O (15 mL), saturated NaHCO3 solution (15 mL), H2O (4 x 30 mL) and brine (30 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to give compound 220 (328 mg, 78%) as a white solid. The obtained product was used in the next step without further purification. 1H NMR (250 MHz, DMSO-d6) 88.52 (brs, 1H, NH), 8.17 (t, J= 1.6 Hz, 1H, CH), 7.85 (dddd, J = 10.8, 7.8, 1.7, 1.1 Hz, 2H, 2 x CH), 7.27 (td, J = 7.8, 0.4 Hz, 1H, CH), 2.77 (d, J = 4.6 Hz, 3H, CH3). All spectral data corresponded to the literature values found in Sun X. et al., Chem. Commun., 2020, 56, 1298-1301.

3-(3-aminophenoxy)-N-methylbenzamide (221)

The reaction was carried out as described in the general procedure. Using iodoaryl ether220 (274 mg, 1.05 mmol, 1.0 equiv.), 3-aminophenol (138 mg, 1.26 mmol, 1.2 equiv.), copper(I) iodide (10 mg, 0.05 mmol, 5 mol %), 2-picolinic acid (14 mg, 0.11 mmol, 10 mol %) and K3PO4 (446 mg, 2.10 mmol, 2.0 equiv.) in dry DMSO (2.1 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM/MeOH from 100 to 98/2 to afford compound221 (184 mg, 72%) as an orange oil. Rf (DCM/MeOH 95/5) 0.29. 1H NMR (250 MHz, CDCb) 87.44 (dt, J = 7.7, 1.4 Hz, 1H, CH), 7.38 - 7.35 (m, 1H, CH), 7.30 (t, J = 7.9 Hz, 1H, CH), 7.12 - 7.01 (m, 2H, 2 x CH), 6.57 (brs, 1H, NH), 6.40 (ddd, J = 8.0, 2.2, 0.9 Hz, 1H, CH), 6.34 (ddd, J = 8.0, 2.3, 0.9 Hz, 1H, CH), 6.26 (t, J = 2.2 Hz, 1H, CH), 3.73 (brs, 2H, NH2), 2.91 (d, J= 4.8Hz, 3H, CH3). HRMS (EI-MS) m/z calcd. for C14H15N2O2 [M+H]+: 243.1128, found: 243.1132.

Example 111: 4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-W-(3-(methylcarbamoyl)phenoxy)phenyl)-3,6-dihydropyridin-1(2H) -carboxamide (222)

The reaction was carried out as described in the general procedure using aniline 221 (76 mg, 0.29 mmol, 1.0 equiv.), 4-nitrophenyl chloroformate (70 mg, 0.35 mmol, 1.2 equiv.), DIPEA (182 pl, 1.05 mmol, 2.4 equiv.) and amine 4 (100 mg, 0.35 mmol, 1.2 equiv.) in dry THF (4.0 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of DCM/MeOH from 98/2 to 95/5 to afford compound 222 (57 mg, 41%) as a white powder. Rf (DCM/MeOH 95/5) 0.31. Mp: degradation 190 °C.<1>H NMR (250 MHz, DMSO-d<a>) 5 11.84 (s, 1H, NH), 8.70 (brs, 1H, NH), 8.64 (s, 1H, CH), 8.47 (d, J = 4.7 Hz, 1H, NH), 7.60 (dt, J = 7.8, 1.3 Hz, 1H, CH), 7.54 - 7.42 (m, 2H, 2 x CH), 7.37 - 7.22 (m, 5H, 4 x CH), 7.17 (ddd, J = 8.0, 2.6, 1.1 Hz, 1H, CH), 6.67 - 6.61 (m, 1H, CH), 6.07 - 5.99 (m, 1H, CH), 4.20 (d, J= 3.1 Hz, 2H, CH<2>), 3.71 (t, J= 5.6 Hz, 2H, CH<2>), 2.76 (d, J= 4.4 Hz, 3H, CH<3>), 2.66 (brs, 2H, CH<2>), 2.21 (s, 3H, CH<3>). HRMS (EI-MS) m/z calcd. for C<27>H<27>N<6>O<3>[M+H]<+>: 483.2139, found: 483.2148.

Subfamily 1.2.

3-Methylpyrolopyrimidine derivatives with one hydropyridine substituted

6-methyl-4-(1,1,2,2,3,3,4,4,4-nonafluorobutylsulfonyloxy)-3,6-dihydro-2H-pyridine-1-carboxylate tert-butyl ester (43a) and 2-methyl-4-(1,1,2,2,3,3,4,4,4-nonafluorobutylsulfonyloxy)-3,6-dihydro-2H-pyridine-1-carboxylate tert-butyl ester (43b)

DBU (1.96 mL, 13.1 mmol, 1.4 equiv.) and perfluoro-1-butanesulfonyl fluoride (1.68 mL, 9.4 mmol) were added dropwise to a solution of N-Boc-2-methyl-piperidone (2.0 g, 9.4 mmol) in anhydrous THF (60 mL) at 0 °C under argon atmosphere. The mixture was allowed to warm to room temperature and stirred overnight. TLC monitoring the next day was performed to ensure complete conversion (if not complete DBU (0.25 equiv.) and perfluoro-1-butanesulfonyl fluoride (0.5 equiv.) were added every 1.5 h). The reaction mixture was then treated with saturated aqueous NaHCO3 solution (50 mL) and extracted with Et2O (2 x 100 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel using a gradient solvent system of PE/EtOAc from 100/0 to 95/5 to afford compounds 43a-43b (4.03 g, 87%) as a colorless oil containing a mixture of diastereoisomers (7/3). Rf(PE/EtOAc 70/30) 0.37. Product43a(main product) 1H NMR (250 MHz, CDCb) 5 5.72 (m, 1H, CH), 4.78 - 4.57 (m, 1H, CH), 4.32 - 4.15 (m, 1H, CH), 3.08 - 2.89 (m, 1H, CH), 2.67 - 2.48 (m, 1H, CH), 2.26 - 2.13 (m, 1H, CH), 1.47 (s, 9H, 3 xC H3), 1.23 (d, J= 6.8 Hz, 3H, CH3). Product43b1H NMR (250 MHz, CDCla) 8 5.76 (m, 1H, CH), 4.78 - 4.57 (m, 1H, CH), 4.51 - 4.34 (m, 1H, CH), 3.63 (ddt, J = 18.8 Hz, J = 4.7 Hz, J = 2.5 Hz, I H, CH), 2.87 - 2.72 (m, 1H, CH), 2.11 - 2.00 (m, 1H, CH), 1.46 (s, 9H, 3 x CH3), 1.17 (d, J = 6.9 Hz, 3H, CH3). HRMS (EI-MS): m/z calcd. for C15H19F9NO5S [M+H]+: 496.0835, found: 496.0835.

6-met¡l-4-(4,4,5,5-tetramet¡l-1,3,2-d¡oxaborolan-2-¡l)-3,6-d¡hydrop¡r¡d tert-butyl n-1(2H)-carboxylate (44a) and 2-methyl-4- (4,4,5,5-tetramet¡l-1,3,2-d¡oxaborolan-2-¡l)-3,6-di¡hydro¡r¡d¡n-1(2H)- Fert-butyl carboxylate (44b)

To a solution of 43a-43b (5.0 g, 10.0 mmol) in 1,4-dioxane (50 ml) was added bis(pinacolato)diboron (2, 9 g, I I, 5 mmol, 1.15 equiv.), potassium acetate (3.5 g, 35.2 mmol, 3.5 eq.) and dppf (170 mg, 0.3 mmol, 0.03 eq.). The solution was degassed for 15 min and Pd(dppf)CbDCM (245 mg, 0.3 mmol, 0.03 equiv.) was added. The mixture was then heated at 80 °C overnight, cooled and extracted with EtOAc (2 x 200 mL). The combined organic phases were washed with brine (100 mL), dried over MgSO4 , filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography using a 95/5 PE/EtOAc solvent system to provide compounds 44b-44b (3.77 g, 83%) as a colorless oil containing a mixture of diastereomers (7/3).Rf(PE/EtOAc 90/10) 0.19. Product44a(main) 1H NMR (250 MHz, CDCb) 86.41 - 6.33 (m, 1H, CH), 4.53 - 4.34 (m, 1H, CH), 4.12 - 3.94 ( m, 1H, CH), 2.82 - 2.63 (m, 1H, CH), 2.26 - 2.09 (m, 2H, 2 x CH), 1.44 (s, 9H, 3 x CH3), 1.25 (s, 12H, 4 x CH3), 1.17 (d, J = 6.9 Hz, 3H, CH3) . Product44b1H NMR (250 MHz, CDCb) 8 6.48 - 6.42 (m, 1H, CH), 4.53 - 4.34 (m, 1H, CH), 4.20 (dt, J = 20.2 Hz, J = 3.8 Hz, 1H, CH), 3.66 - 3.51 (m, 1H, CH), 2.50 - 2.34 (m, 1H, CH), 2.09 - 1.98 (m, 1H, CH), 1.44 (s, 9H, 3 x CH3), 1.25 (s, 12H, 4 x CH3), 1.04 (d, J = 6.8 Hz, 3H, CH3). HRMS (EI-MS) m/z calcd. for C17H31BNO4 [M+H]+: 324.2341, found: 324.2342.

6-met¡l-4-(5-met¡l-7H-pyrrole[2,3-d]p¡r¡m¡d¡n-4-¡l)-3,6-d¡h drop¡r¡d¡n-1(2H)-ferc-butyl carbox¡late (45a) and 2-met¡l-4-(5-met¡l-7H-pyrrole[2,3-d]p¡r¡m¡n-4-¡l)-3,6-d¡h Ferc-butyl drop¡r¡d¡n-1(2H)-carboxylate (45b)

The reaction was carried out as described in the general procedure using chlorinated bicycle 2 (0.4 g, 2.4 mmol) and boronate ester 44b-44b (850 mg, 2.6 mmol, 1.1 equiv.) in THF (12 mL). The crude mixture was purified by column chromatography on silica gel using a gradient solvent system of CH 2 Ch /acetone from 90/10 to 70/30 to provide compounds 45a-45b (1.25 g, 80%) as a white solid containing a mixture of diastereomers (7/3). Rf (PE/EtOAc 70/30) 0.18. Mp: 161 - 163 °C. Product35a(main) 1H NMR (250 MHz, MeOD-d4) 88.59 (s, 1H, CH), 7.18 (d, J = 1.0 Hz, 1H, CH), 5.90 - 5.86 (m, 1H, CH), 4.76 - 4.57 (m, 1H, CH), 4.22 (dd, J = 13.3 Hz, J = 4.8 Hz, 1H, CH), 3.21 - 3.00 (m, 1H, CH), 2.70 - 2.52 (m, 1H, CH), 2.51 - 2.37 (m, 1H, CH), 2.24 (d, J = 1.1 Hz, 3H, CH3), 1.49 (s, 9H, 3 x CH3), 1.31 (d, J= 6.8 Hz, 3H, CH3). Product35b1H NMR (250 MHz, MeOD-d4) 88.59 (s, 1H, CH), 7.18 (d, J= 1.0 Hz, 1H, CH), 5.95 - 5.90 (m, 1H, CH), 4.76-4.57 (m, 1H, CH), 4.42 (dt, J = 19.5 Hz, J = 3.3 Hz, 1H, CH), 3.87 - 3.69 (m, 1H, CH), 2.94 - 2.77 (m, 1H, CH), 2.51 - 2.37 (m, 1H, CH), 2.24 (d, J = 1.1 Hz, 3H, CH3), 1.49 (s, 9H, 3xCH3), 1.25 (d, J = 6.8Hz, 1H, CH3). HRMS (EI-MS) m/z calcd. for C18H25N4O2 [M+H]+: 329.1972, found: 329.1972.

5-Methyl-4-(6-methyl-1,2,3,6-tetrahydrochloridin-4-l)-7H-pyrrole[2] trifluoroacetate ,3-d]pyrmádina (46a) and 5-trifluoroacetate met¡l-4-(2-met¡l-1,2,3,6-tetrah¡drop¡r¡d¡n-4-¡l)-7H-p¡rrolo[2,3-d]p ¡r¡m¡d¡na (46b)

The reaction was carried out as described in general procedure F2 using N-boc protected compound 45b-45b (0.6 g, 1.8 mmol) and TFA (4.9 mL, 63.9 mmol, 35.0 equiv.) in CH 2 Cl 2 (50 mL). The reaction was complete after 1 h. Work-up gave compounds 46a-46b (0.44 g, 72%) as an off-white solid containing a mixture of diastereomers (7/3). Mp: 199 - 201 °C. Product46a(main) 1H NMR (250<m>H<z>, MeOD-d4) 88.60 (s, 1H, CH), 7.21 (d, J = 1.2 Hz, 1H, CH), 5.92 - 5.85 (m, 1H, CH), 3.70 - 3.58 (m, 1H, CH), 3.34 -3.21 (m, 1H, CH), 3.10 - 2.95 (m, 1H, CH), 2.61 - 2.50 (m, 2H, 2 x CH), 2.32 (d, J= 1.2 Hz, 3H, CH3), 1.31 (d, J= 7.0 Hz, 3H, CH3). 19F NMR (235 MHz, MeOD-d4) 8 -76.9 (s). Product46b1H NMR (250 MHz, MeOD-d4) 88.60 (s, 1H, CH), 7.21 (d, J = 1.2 Hz, 1H, CH), 6.03 - 5.95 (m, 1H, CH), 3.70 - 3.58 (m, 1H, CH), 3.33 - 3.29 (m, 1H, CH), 3.10 - 2.95 (m, 1H, CH), 2.71 - 2.59 (m, 1H, CH), 2.30 (d, J = 1.2 Hz, 3H, CH3), 2.28 - 2.14 (m, 1H, CH), 1.26 (d, J = 7.0 Hz, 3H, CH3). 19F NMR (235 MHz, DMSO-d4) 8 -76.9 (s). HRMS (EI-MS) m/z calcd. for C13H18N4 [M+H]+: 229.1448, found: 229.1447.

Example 30: W-(3-fluorophen¡l)-6-methyl¡l-4-(5-methyl-7H-pyrrole[2,3-d]pyr¡m¡d¡n- 4-¡l)-3,6-di¡hydro¡r¡din-1(2H)-carboxamide (47a) and N-(3-fluorophen¡l)-2-methyl¡l-4-(5-methyl¡l-7H-pyrrole[2,3-d]pyr¡m¡d¡n-4-¡ l)-3,6-di¡hydro¡r¡d¡n-1 (2 H)-carboxamide (47b)

The reaction was carried out as described in the general procedure using amine 46a-46b (70 mg, 0.20 mmol) in anhydrous CH 2 Cl 2 (5 mL). The crude reaction mixture was purified by column chromatography on silica gel using a gradient solvent system of CH 2 Ch 2 /acetone from 90/10 to 70/30 to provide compounds 47a-47b (61 mg, 84%) as a white solid containing a mixture of diastereomers (7/3). R f (CH 2 Ch 2 /acetone 50/50) 0.28. Mp: 154 - 156 °C. Product47a(main) 1H NMR (400 MHz, MeOD-d4) 88.62 (s, 1H, CH), 7.32 (dt, J = 11.6 Hz, J = 2.2 Hz, 1H, CH), 7.29 - 7.22 (m, 2H, 2 x CH), 7.19 (ddd, J = 8.2 Hz, J = 2.1 Hz, J = 1.1 Hz, 1H, CH), 6.73 (tdd, J = 8.4 Hz, J = 2.5 Hz, J = 1.1 Hz, 1H, CH), 6.03 - 5.99 (m, 1H, CH), 4.96 - 4.88 (m, 1H, CH), 4.32 (dd, J = 13.7 Hz, J = 5.4 Hz, 1H, CH), 3.38 - 3.27 (m, 1H, CH), 2.83 - 2.69 (m, 1H, CH), 2.63 - 2.56 (m, 1H, CH), 2.32 (d, J = 1.2 Hz, 3H, CH3), 1.42 (d, J = 6.8 Hz, 3H, CH3). 19F NMR (376 MHz, DMSO-d4) 8 -115.0 (s). Product47b1H NMR (400 MHz, MeOD-d4) 8 8.63 (s, 1H, CH), 7.32 (dt, J = 11.6 Hz, J = 2.2 Hz, 1H, CH), 7.29 - 7.22 (m, 2H, 2 x CH), 7.19 (ddd,J =8.2 Hz,J =2.1 Hz,J =1.1 Hz, 1H, CH), 6.73 (tdd,J =8.4 Hz, J = 2.5 Hz, J = 1.1 Hz, 1H, CH), 6.07 - 6.04 (m, 1H, CH), 4.87 - 4.79 (m, 1H, CH), 4.54 (dt, J = 19.0 Hz, J = 3.7 Hz, 1H, CH), 4.07 - 3.89 (m, 1H, CH), 3.07 - 2.92 (m, 1H, CH), 2.58 - 2.51 (m, 1H, CH), 2.32 (d, J = 1.2 Hz, 3H, CHa), 1.36 (d, J = 6.8 Hz, 3H, CHa). 19F NMR (376 MHz, DMSO-d4) 8 -76.9 (s). HRMS (EI-MS) m/z calcd. for C20H21FN5O [M+H]+: 366.1725, found: 366.1723.

Example 31: W-(3-chlorophen¡l)-6-met¡l-4-(5-met¡l-7H-pyrrole[2,3-d]pyr¡m¡d¡n- 4-¡l)-3,6-di¡hydro¡r¡din-1(2H)-carboxamide (48a) and W-(3-chlorophen¡l)-2-methyl¡l-4-(5-methyl¡l-7H-pyrrole[2,3-d]pyr¡m¡d¡n-4-¡ l)-3,6-di¡hydro¡r¡d¡n-1(2H)-carboxamide (48 b)

The reaction was carried out as described in the general procedure using amine 46a-46b (70 mg, 0.20 mmol) in anhydrous CH 2 Cl 2 (5 mL). The crude reaction mixture was purified by column chromatography on silica gel using a gradient solvent system of CH 2 Cl 2 /acetone from 90/10 to 70/30 to provide compounds 48a-48b (43 mg, 56%) as a white solid containing a mixture of diastereomers (7/3). Rf (CH 2 Cl 2 /acetone 50/50) 0.31. Mp: 159 - 161 °C. Product48a(main) 1H NMR (400 MHz, MeOD-d4) 88.62 (s, 1H, CH), 7.56 (t, J = 2.0 Hz, 1H, CH), 7.36 - 7.30 (m, 1H, CH), 7.27 - 7.19 (m, 2H, 2 x CH), 7.04 - 6.93 (m, 1H, CH), 6.02 - 5.97 (m, 1H, CH), 4.97 - 4.86 (m, 1H, CH), 4.31 (dd, J = 13.7 Hz, J = 5.3 Hz, 1H, CH), 3.38 - 3.26 (d, J = 3.8 Hz, 1H, CH), 2.83 - 2.69 (m, 1H, CH), 2.63 - 2.57 (m, 1H, CH), 2.34 - 2.29 (m, 3H, CH3), 1.42 (d, J= 6.7 Hz, 3H, CH3). Product48b1H NMR (400 MHz, MeOD-d4) 88.63 (s, 1H, CH), 7.56 (t, J = 2.0 Hz, 1H, CH), 7.36 - 7.30 (m, 1H, CH), 7.27 - 7.19 (m, 2H, 2 x CH), 7.04 - 6.93 (m, 1H, CH), 6.08 - 6.03 (m, 1H, CH), 4.85 - 4.77 (m, 1H, CH), 4.54 (dt, J = 18.9 Hz, J= 3.6 Hz, 1H, CH), 4.03 - 3.91 (m, 1H, CH), 3.05 - 2.94 (m, 1H, CH), 2.57 - 2.50 (m, 1H, CH), 2.34 - 2.29 (m, 3H, CH3), 1.36 (d, J = 6.7 Hz, 3H, CH3). HRMS (EI-MS) m/z calcd. for C20H21ClNaO [M+H]+: 382.1429, found: 382.1426.

Example 32: W-(3-bromophen¡l)-6-methyl¡l-4-(5-methyl¡l-7H-pyrrole[2,3-d]pyr¡m¡d¡n- 4-¡l)-3,6-di¡hydro¡r¡din-1(2H)-carboxamide (49a) and W-(3-bromophen¡l)-2-met¡l-4-(5-met¡l-7H-pyrrole[2,3-d]p¡r¡m¡d¡n-4-¡ l)-3,6-di¡hydro¡r¡d¡n-1(2H)-carboxamide (49b)

The reaction was carried out as described in the general procedure using amine 46a-46b (70 mg, 0.20 mmol) in anhydrous CH 2 Cl 2 (5 mL). The crude reaction mixture was purified by column chromatography on silica gel using a gradient solvent system of CH 2 Ch 2 /acetone from 90/10 to 70/30 to provide compounds 49a-49b (61 mg, 71%) as a white solid containing a mixture of diastereomers (7/3). R f (CH 2 Ch 2 /acetone 50/50) 0.31. Mp: 159 - 161 °C. Product49a(main) 1H NMR (400 MHz, MeOD-d4) 88.62 (s, 1H, CH), 7.72 - 7.70 (m, 1H, CH), 7.37 (dt, J = 7.3 Hz, J= 2.1 Hz, 1H, CH), 7.25 - 7.22 (m, 1H, CH), 7.21 - 7.13 (m, 2H, 2 x CH), 6.03 - 5.99 (m, 1H, CH), 4.96 - 4.88 (m, 1H, CH), 4.31 (dd, J = 13.7 Hz, J= 5.3 Hz, 1H, CH), 3.38 - 3.26 (m, 1H, CH), 2.82 - 2.69 (m, 1H, CH), 2.64 - 2.51 (m, 1H, CH), 2.32 (d, J = 1.3 Hz, 3H, CH3), 1.42 (d, J = 6.7 Hz, 3H, CH3). Product49b1H NMR (400 MHz, MeOD-d4) 88.63 (s, 1H, CH), 7.72 - 7.70 (m, 1H, CH), 7.37 (dt, J = 7.3 Hz, J= 2.1 Hz, 1H, CH), 7.25 - 7.22 (m, 1H, CH), 7.21 - 7.13 (m, 2H, 2 x CH), 6.08 - 6.03 (m, 1H, CH), 4.87 - 4.74 (m, 1H, CH), 4.54 (dt, J = 18.9 Hz, J = 3.6 Hz, 1H, CH), 4.04 - 3.92 (m, 1H, CH), 3.06 -2.93 (m, 1H, CH), 2.64 - 2.51 (m, 1H, CH), 2.32 (m, 3H, CH3), 1.36 (d, J = 6.8 Hz, 3H, CH3). HRMS (EI-MS) m/z calcd. for C20H21BrNaO [M+H]+: 426.0924, found: 426.0921.

dimethyl 2.6-dimethyl-4-oxopyperidin-3,5-dicarboxylate (50)

Ammonia gas was bubbled through a mixture of dimethyl 1,3-acetonecarboxylate (19.0 g, 109 mmol) and acetaldehyde (12.5 mL, 284 mmol, 2.6 equiv.) at -30 °C until the liquid was saturated. The solution was stored in the freezer (4 °C) for 20 h. After evaporation of the solvent under reduced pressure, the yellow residue was purified by column chromatography on silica gel using a gradient solvent system of PE/EtOAc from 100/0 to 70/30 to provide compound 50 (14.0 g, 53%) as an orange oil. 1H NMR (250 MHz, CDCb) 83.74 - 3.65 (m, 8H, 2 x CH 2 x OCH3), 2.97 - 2.91 (m, 2H, 2 x CH), 1.26 - 1.23 (d, J = 6.6 Hz, 3H, CH3), 1.15 - 1.09 (d, J = 6.6 Hz, 3H, CH3) (see document WO2015158283, 2015, page 172).

2,6-dimet¡lp¡perídin-4-one hydrochloride (51)

A solution of 50 (14.0 g, 65 mmol) in 10% aqueous HCl solution (100 mL) was heated to 110 °C for 24 h. The solution was cooled and the solvent was removed under reduced pressure to afford compound 51 (8.5 g, 80%) as an orange solid which was used in the next step without further purification. 1H NMR (250 MHz, DMSO-de) 810.11 - 9.79 (m, 2H, NH H+), 3.91 - 3.74 (m, 1H, CH), 3.61 - 3.43 (m, 1H, CH), 2.77 - 2.60 (m, 2H, CH2), 2.48 -2.35 (m, 2H, CH2), 1.35 (d, J = 6.4 Hz, 3H, CH3), 1.30 (d, J= 6.7 Hz, 3H, CH3). Document WO2015158283, 2015, pp. 172.

tert-butyl 2.6-dimethyl-4-oxopyperidin-1-carboxylate (52)

Na2CO3 (11.0 g, 104 mmol, 2.0 equiv.) was added portionwise to a solution of 51 (8.5 g, 52 mmol) in 1,4-doxane (70 mL) and H2O (70 mL). Boc2O (22.7 g, 104 mmol, 2.0 equiv.) was then added, and the resulting reaction mixture was stirred at room temperature for 24 h. The solvent was removed under reduced pressure, and the resulting aqueous solution was extracted with Et2O (3 x 200 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude mixture was purified by column chromatography on silica gel using a gradient solvent system of PE/EtOAc from 97/3 to 80/20 to provide compound 122 (2.5 g, 21%) as an off-white solid containing a mixture of diastereomers (Trans/Cis, 9/1). Major isomer (trans)52:<1>H NMR (250 MHz, CDCl<3>) 84.44 - 4.23 (m, 2H, 2 x CH), 2.83 (dd, J = 17.8 Hz, J = 6.4 Hz, 2H, 2 x CH), 2.35 (dd, J = 17.8 Hz, J = 1.9 Hz, 2H, 2 x CH), 1.48 (s, 9H, 3 x CH<3>), 1.23 (dd, J= 6.8 Hz, J= 0.7 Hz, 6H, 2 x CH<3>). Document WO2015158283, 2015, pp. 172.

2,6-dimethyl-4-((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester (53)

A 1 M solution of NaHMDS in THF (5.7 mL, 5.72 mmol, 1.3 equiv.) was added dropwise to a solution of 52 (1.0 g, 4.40 mmol) in anhydrous THF (25 mL) at -78 °C under argon. The solution was stirred at this temperature for 1 h and then a solution of N-phenyl-bis(trifluoromethanesulfonimide) (1.89 g, 5.28 mmol, 1.2 equiv.) in THF (12 mL) was slowly added. The reaction mixture was allowed to warm to room temperature and stirred for 2.5 h. The solvent was removed under reduced pressure and the residue was suspended in Et<2>O (40 mL) and washed with cold water (2 x 10 mL). The ether layers were dried with MgSO<4>, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel using a 99/1 PE/EtOAc solvent system to afford compound 53 (0.98 g, 62%) as an off-white solid containing the trans product as an enantiomeric mixture.<1>H NMR (250 MHz, CDC<b>) 85.82 - 5.77 (m, 1H, CH), 4.42 - 4.27 (m, 2H, 2 x CH), 2.91 - 2.77 (m, 1H, CH), 2.17 (dd, J = 16.5 Hz, J = 2.8 Hz, 1H, CH), 1.48 (s, 9H, 3 x CH<3>), 1.36 (d, J = 6.3 Hz, 3H, CH<3>), 1.25 - 1.21 (d, J = 6.3 Hz, 3H, CH<3>). Heterocycles, 1996, 43, 10, 2131-2138.

2.6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester (54)

To a solution of 53 (1.0 g, 2.78 mmol) in 1,4-dioxane (20 mL) was added bis(pinacolato)diboron (0.78 g, 3.06 mmol, 1.1 equiv.), potassium acetate (0.82 g, 8.34 mmol, 3.0 equiv.) and dppf (46 mg, 0.08 mmol, 0.03 equiv.). The solution was degassed for 15 min and Pd(dppf)C<h>CH<2>C<h>(68 mg, 0.08 mmol, 0.03 equiv.) was added. The mixture was then heated to 80 °C for 12 h, cooled, and extracted with EtOAc (2 x 100 mL). The organic phases were washed with brine (100 mL), dried over MgSO<4>, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel using a solvent system of PE/EtOAc from 95/5 to 70/30 to afford compound 54 (0.72 g, 77%) as a white solid containing the trans product as an enantiomeric mixture.<1>H NMR (250 MHz, CDC<b>) 86.55 (dd, J = 5.0 Hz, J = 2.9 Hz, 1H CH), 4.25 - 4.03 (m, 2H, 2 x CH), 2.41 - 2.27 (m, 1H, CH), 2.14 (ddd, J= 16.0 Hz, J = 2.4 Hz, J = 0.9 Hz, 1H, CH), 1.44 (s, 9H, 3 x CH<3>), 1.26 - 1.21 (m, 15H, 5xCH<3>), 1.02 (dd, J = 6.5 Hz, J = 0.6 Hz, 3H, CH<3>). Document WO2008016534, 2008, p. 133.

2.6-dimethyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester (55)

The reaction was carried out as described in the general procedure using chlorinated bicyclohexane (0.30 g, 1.80 mmol) and boronic acid pinacol ester (54) (0.67 g, 1.98 mmol, 1.1 equiv.) in THF (9 mL). The crude mixture was purified by column chromatography on silica gel using a gradient solvent system of CH<2>Cl<2>/acetone from 100/0 to 70/30 to afford compound 55 (0.43 g, 70%) as a beige solid containing the trans product as an enantiomeric mixture. Rf(CH<2>C<h>/acetone 80/20) 0.26. Mp: degradation 119 °C.<1>H NMR (400 MHz, CDC<b>) 89.81 (brs, 1H, NH), 8.81 (s, 1H, CH), 7.19 - 6.97 (m, 1H, CH), 6.17 (dd, J = 5.2 Hz, J= 2.8 Hz, 1H, CH), 4.51 - 4.40 (m, 2H, 2 x CH), 3.06 - 2.95 (m, 1H, CH), 2.67 (dd, J = 15.9 Hz, J = 2.4 Hz, 1H, CH), 2.35 (d, J = 1.2 Hz, 3H, CH<3>), 1.52 (s, 9H, 3xCH<3>), 1.43 (d, J = 6.4 Hz, 3H, CH<3>), 1.28 (d, J = 6.2 Hz, 3H, CH<3>). HRMS (EI-MS) m/z calcd. for C<19>H<27>N<4>O<2>[M+H]<+>: 343.2129, found: 343.2128.

4-(2,6-dimetN-1,2,3,6-tetrahydropiNdm-4-N)-5-metM-7H-pyrrolo[2,3-d]pinmidma trifluoroacetate (56)

The reaction was carried out as described in General Procedure F1 using the N-Boc protected compound 55 (0.4 g, 1.17 mmol) in CH<2>Cl<2> (32 mL). The reaction was complete after 1 h. Work-up gave compound 56 (0.31 g, 74%) as a light yellow solid containing the trans product as an enantiomeric mixture. Mp: degradation 136 °C.<1>H NMR (400 MHz, DMSO-de) 811.80 (brs, 1H, NH), 8.60 (s, 1H, CH), 7.29 (s, 1H, CH), 5.93 (s, 1H, CH), 3.74 (s, 1H, CH), 3.63 (s, 2H, NH H<+>), 3.22 (s, 1H, CH), 2.60 - 2.53 (m, 1H, CH), 2.29 - 2.19 (m, 4H, CH CH<3>), 1.23 (d, J = 6.9 Hz, 3H, CH<3>), 1.16 (d, J = 5.6 Hz, 3H, CH<3>).<19>F NMR (376 MHz, DMSO-d<6>) 8 -73.5 (s). HRMS (EI-MS) m/z calcd. for C<14>H<19>N<4>[M+H]<+>: 243.1604, found: 243.1603.

Example__________ 33: N-(3-fluorophenyl)-2,6-dimethyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H )-carboxamide (57)

The reaction was carried out as described in the general procedure by using amine 56 (60 mg, 0.25 mmol) in anhydrous CH<2>Cl<2> (4 mL). The crude reaction mixture was purified by column chromatography on silica gel using a gradient solvent system of CH<2>C<h>/acetone from 80/20 to 30/70 to provide compound 57 (51 mg, 54%) as a white solid containing the trans product as an enantiomeric mixture. Rf (CH<2>Cfc/acetone 80/20) 0.11. Mp: 210 - 212 °C.<1>H NMR (400 MHz, DMSO-de) 8 11.84 (brs, 1H, NH), 8.87 (brs, 1H, NH), 8.67 (s, 1H, CH), 7.48 (d, J = 12.0 Hz, 1H, CH), 7.34 (s, 1H, CH), 7.32 - 7.24 (m, 2H, 2 x CH), 6.75 (t, J = 8.1 Hz, 1H, CH), 6.24 - 6.12 (m, 1H, CH), 4.60 - 4.55 (m, 1H, CH), 4.55 - 4.48 (m, 1H, CH), 2.95 (d, J = 14.8Hz, 1H, CH), 2.72 (d, J = 16.0 Hz, 1H, CH), 2.29 (s, 3H, CH<3>), 1.37 (d, J = 6.3 Hz, 3H, CH<3>), 1.19 (d, J = 6.3 Hz, 3H, CH3). 19F NMR (376 MHz, DMSO-d6) 5 - 112.9 (s). HRMS (EI-MS) m/z calcd. for C21H23FN5O [M+H]+: 380.1881, found: 380.1880.

Example__________ 34. W-(3-chlorophenyl)-2,6-dimethyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H )-carboxamide (58)

The reaction was carried out as described in the general procedure by using amine 56 (60 mg, 0.25 mmol) in anhydrous CH 2 Cl 2 (4 mL). The crude reaction mixture was purified by column chromatography on silica gel using a gradient solvent system of CH 2 Cl 2 /acetone from 80/20 to 30/70 to provide compound 58 (72 mg, 73%) as a white solid containing the trans product as an enantiomeric mixture. R (CH 2 Cb/acetone 80/20) 0.10. Mp: 240 - 242 °C. 1H NMR (400 MHz, DMSO-*) 5 11.84 (brs, 1H, NH), 8.84 (brs, 1H, NH), 8.67 (s, 1H, CH), 7.70 (s, 1H, CH), 7.44 (d, J = 8.3 Hz, 1H, CH), 7.34 (s, 1H, CH), 7.27 (t, J = 8.1 Hz, 1H, CH), 6.99 (d, J = 7.9 Hz, 1H, CH), 6.23 - 6.10 (m, 1H, CH), 4.61 - 4.55 (m, 1H, CH), 4.55 - 4.49 (m, 1H, CH), 2.95 (d, J = 17.5Hz, 1H, CH), 2.72 (d, J = 16.0 Hz, 1H, CH3), 2.29 (s, 3H, CH3), 1.37 (d, J = 6.2 Hz, 3H, CH3), 1.19 (d, J = 6.3 Hz, 3H, CH3). HRMS (EI-MS) m/z calcd. for C21H23ClN5O [M+H]+: 396.1586, found: 396.1585.

Example_________ 35. W-(3-bromophenyl)-2,6-dimethyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H )-carboxamide (59)

The reaction was carried out as described in the general procedure by using amine 56 (60 mg, 0.25 mmol) in anhydrous CH 2 Cl 2 (4 mL). The crude reaction mixture was purified by column chromatography on silica gel using a gradient solvent system of CH 2 Cl 2 /acetone from 80/20 to 30/70 to provide compound 59 (77 mg, 71%) as a white solid containing the trans product as an enantiomeric mixture. R (CH 2 Cl 2 /acetone 80/20) 0.11. Mp: 238 - 240 °C. 1H NMR (400 MHz, DMSO-d6) 5 11.84 (brs, 1H, NH), 8.83 (brs, 1H, NH), 8.67 (s, 1H, CH), 7.84 (t, J = 2.0 Hz, 1H, CH), 7.49 (d, J = 8.2 Hz, 1H, CH), 7.33 (s, 1H, CH), 7.21 (t, J = 8.0 Hz, 1H, CH), 7.12 (d, J = 8.0 Hz, 1H, CH), 6.22 - 6.11 (m, 1H, CH), 4.64 - 4.47 (m, 2H, 2 x CH), 3.00 -2.88 (m, 1H, CH), 2.72 (d, J = 16.0 Hz, 1H, CH), 2.29 (s, 3H, CH3), 1.36 (d, J = 6.3 Hz, 3H, CH3), 1.19 (d, J = 6.3 Hz, 3H, CH3). HRMS (EI-MS) m/z calcd. for C21H23BrN5O [M+H]+: 440.1080, found: 440.1081.

Example___________ 36: 2,6-dimethyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(3-phenoxyphenyl)-3,6-dihydropyridin-1(2H )-carboxamide (60)

The reaction was carried out as described in the general procedure by using amine 56 (60 mg, 0.25 mmol) in anhydrous CH 2 Cl 2 (4 mL). The crude reaction mixture was purified by column chromatography on silica gel using a gradient solvent system of CH 2 Cl 2 /acetone from 80/20 to 30/70 to provide compound 60 (56 mg, 49%) as a white solid containing the trans product as an enantiomeric mixture. R (CH 2 Cb/acetone 80/20) 0.15. Mp: 212 - 214 °C. 1H NMR (400 MHz, DMSO-*) 5 11.84 (brs, 1H, NH), 8.76 (brs, 1H, NH), 8.66 (s, 1H, CH), 7.47 - 7.22 (m, 6H, 6xCH), 7.13 (t, J= 7.2 Hz, 1H, CH), 7.02 (d, J= 7.9 Hz, 2H, 2 x CH), 6.60 (d, J= 8.0 Hz, 1H, CH), 6.15 (s, 1H, CH), 4.62 - 4.52 (m, 1H, CH), 4.52 - 4.44 (m, 1H, CH), 2.92 (d, J= 15.9 Hz, 1H, CH), 2.69 (d, J= 16.1 Hz, 1H, CH), 2.28 (s, 3H, CH3), 1.34 (d, J = 6.2 Hz, 3H, CH3), 1.17 (d, J = 6.3 Hz, 3H, CH3). HRMS (EI-MS) m/z calcd. for C27H28N5O2 [M+H]+: 454.2238, found: 454.2238.

Family 2.

Pyrolopyrimidine derivatives not substituted with a hydropyridine.

tert-Butyl 4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridin-1(2H)-carboxylate (61)

The reaction was carried out as described in the general procedure using 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.60 g, 3.91 mmol) and N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (1.3 g, 4.30 mmol, 1.1 equiv.) in THF (10 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Cl2/acetone from 90/10 to 50/50. To remove final impurities, the product was precipitated from acetone/pentane mixture to afford compound61 (0.85 g, 72%) as a pale yellow solid. Rf(CH2Cl2/acetone 70/30) 0.43. Mp: 159 - 161 °C. 1H NMR (400 MHz, MeOD-d4)58.64 (s, 1H, CH), 7.42 (d, J = 3.7 Hz, 1H, CH), 6.77 - 6.73 (m, 1H, CH), 6.72 (d, J = 3.6 Hz, 1H, CH), 4.21 - 4.15 (m, 2H, CH2), 3.66 (t, J = 5.7 Hz, 2H, CH2), 2.78 - 2.71 (m, 2H, CH2), 1.49 (s, 9H, 3 x CH3). HRMS (EI-MS) m/z calcd. for C16H21N4O2 [M+H]+: 301.1659, found: 301.1659.

4-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine dihydrochloride (62)

The reaction was carried out as described in the general procedureJ with the N-Boc protected compound61 (100 mg, 0.28 mmol). The reaction mixture was stirred for 1 h at room temperature. Upon completion, Et2O (20 mL) was added and the resulting precipitate was filtered and washed with Et2O (3 x 10 mL) to afford compound62 (87 mg, 96%) as a light brown solid. Mp: degradation > 260 °C. 1H NMR (400 MHz, DMSO-d6) 512.91 (brs, 1H, NH), 9.63 (brs, 2H, NH H+), 8.98 - 8.82 (m, 1H, CH), 7.93 - 7.76 (s, 1H, CH), 7.07 - 6.91 (m, 2H, 2 x CH), 4.57 - 4.08 (m, 1H, H+), 3.96 - 3.86 (s, 2H, CH2), 3.44 - 3.26 (s, 2H, CH2), 3.12 - 2.87 (s, 2H, CH2). HRMS (EI-MS) m/z calcd. for C11H13N4 [M+H]+: 201.1135, found: 201.1135.

Example 37: N-(3-chlorophenyl)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydro-pyridin-1 (2H)-carboxamide (63)

The reaction was carried out as described in the general procedure using amine62 (70 mg, 0.26 mmol). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Cl2/acetone from 100/0 to 50/50 to afford compound63 (64 mg, 71%) as a white solid. Rf (CH2Cl2/acetone 50/50) 0.29. Mp: degradation 122 °C. 1H NMR (250 MHz, MeOD-d4)58.68 (s, 1H, CH), 7.57 (t, J = 2.0 Hz, 1H, CH), 7.48 (d, J = 3.6 Hz, 1H, CH), 7.33 (ddd, J = 8.2 Hz, J = 2.0 Hz, J = 1.2 Hz, 1H, CH), 7.24 (t, J= 8.0 Hz, 1H, CH), 7.01 (ddd, J = 7.7 Hz, J = 2.1 Hz, J = 1.2 Hz, 1H, CH), 6.90 - 6.83 (m, 1H, CH), 6.82 (d, J = 3.6 Hz, 1H, CH), 4.41 - 4.28 (m, 2H, CH2), 3.82 (t, J = 5.6 Hz, 2H, CH2), 2.96 - 2.82 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for C18H17ClN5O [M+H]+: 354.1116, found: 354.1114.

Family 3.

3-Chloropyrolopyrimidine derivatives with hydropyridine.

4-(5-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydro-2H-pyridine-1-carboxylate tert-butyl ester (64)

N-Chlorosuccinimide (222 mg, 1.66 mmol, 1.0 equiv.) was added to a solution of 61 (500 mg, 1.66 mmol) in anhydrous DMF (0.047 M). The reaction mixture was heated to 70 °C and stirred for 4 h until completion (TLC monitoring). After cooling, it was poured into water and the aqueous phase was extracted with EtOAc (2 × 100 mL). The combined organic phases were washed with brine (4 × 200 mL) and saturated sodium thiosulfate solution, dried over MgSO, filtered, and concentrated. The residue was purified by silica gel column chromatography using a gradient solvent system of CH2Ch/acetone from 100/0 to 60/40 to afford compound64 (340 mg, 61%) as a white solid. Rf (CH2Cl2/acetone 70/30) 0.41. Mp: degradation 189 °C. 1H NMR (250 MHz, MeOD-d4) 58.69 (s, 1H, CH), 7.51 (s, 1H, CH), 6.11 (s, 1H, CH), 4.17 (q, J= 2.8 Hz, 2H, CH2), 3.71 (t, J= 5.6 Hz, 2H, CH2), 2.66 (m, 2H, CH2), 1.50 (s, 9H, CH3). HRMS (EI-MS) m/z calcd. for C16H20ClN4O2 [M+H]+: 335.1269, found: 335.1272.

5-chloro-4-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (65)

The reaction was carried out as described in the general procedure Jusando 64 (250 mg, 0.75 mmol). The desired product 65 (195 mg, 85 %) was obtained as a white solid. Rf (CH 2 Cl 2 / MeOH 80/20) 0.03. Mp: degradation > 266 °C. 1H NMR (400 MHz, DMSO-ri?) 5 13.07 (s, 1H, NH), 9.70 (s, 2H, NH 2 (sel)), 8.88 (s, 1H, CH), 7.95 (s, 1H, CH), 6.27 (s, 1H, CH), 3.86 (s, 2H, CH 2), 3.42 - 3.21 (s, 2H, CH 2), 2.88 (s, 2H, CH 2). HRMS (EI-MS) m/z calcd. for CnH 12ClN4[M+H]+: 235.0745, found: 235.0743.

Example 38: [3-[[4-(5-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydro-2H-pyridine-1) W,W-dimethylcarbamate carbonyl]amino]phenyl (66)

The reaction was carried out as described in the general procedure using 3-aminophenyl dimethylcarbamate (24 mg, 0.14 mmol) and 65 (50 mg, 0.16 mmol, 1.2 equiv.). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Cl 2 /acetone from 10/0 to 60/40 to provide compound 66 (42 mg, 70%) as a white solid. Rf (CH 2 Cl 2 /acetone 50/50) 0.25. Mp: degradation 132 °C. 1H NMR (250 MHz, DMSO-ri?) 512.53 (s, 1H, NH), 8.77 (s, 1H, CH), 8.69 (s, 1H, NH), 7.79 (t, J= 2.1 Hz, 1H, CH), 7.42 - 7.28 (m, 2H, 2 x CH), 7.22 (t, J = 8.0 Hz, 1H, CH), 6.69 (d, J = 8.3 Hz, 1H, CH), 6.22 (s, 1H, CH), 4.25 (s, 2H, CH2), 3.73 (t, J = 5.5 Hz, 2H, CH2), 3.03 (s, 3H, NCH3), 2.90 (s, 3H, NCH3), 2.71 (s, 2H, CH2). HRMS (EI-MS) m/z calcd. for C21H22ClNaO3 [M+H]+: 441.1436, found: 441.1436.

Family 4.

Derivatives of 3-cyclopropylpyrrolopyrimidine with an unsubstituted hydropyridine.

4-(5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester (67)

To a solution of 1461 (1.40 g, 4.66 mmol) in anhydrous DMF (25 mL) under argon was added NIS (1.10 g, 4.89 mmol, 1.05 equiv.) at 0 °C. The mixture was stirred at this temperature for 20 min and allowed to warm to room temperature. The solution was poured onto ice (50 g) and the aqueous phase was extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with saturated NaCl solution (4 x 50 mL), dried over MgSO, filtered, and concentrated under reduced pressure. The crude residue was dissolved in a minimum of acetone, precipitated with pentane, and filtered to afford compound 67 (1.79 g, 90%) as a light brown solid.

Rf(CH2Cl2/acetone 70/30) 0.16. Mp: 151 - 153 °C. 1H NMR (400 MHz, MeOD-d4) 88.67 (s, 1H, CH), 7.61 (s, 1H, CH), 6.02 - 5.92 (m, 1H, CH), 4.25 - 4.14 (m, 2H, CH2), 3.73 (t, J= 5.6 Hz, 2H, CH2), 2.62 - 2.52 (m, 2H, CH2), 1.49 (s, 9H, 3 x CH3). HRMS (EI-MS) m/z calcd. for C16H20 IN4O2 [M+H]+: 427.0625, found: 427.0626.

4-(5-iodo-7-tosyl-7-pyrrolo[2,3-d]pyrimidin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester (68)

NaH (60% dispersion in mineral oil, 0.18 g, 4.50 mmol, 1.2 equiv.) was added to a solution of the iodide derivative 67 (1.60 g, 3.75 mmol) in anhydrous THF (35 mL) under argon at room temperature. The solution was stirred for 30 min before the addition of p-toluenesulfonyl chloride (0.79 g, 4.13 mmol, 1.1 equiv.). Stirring was continued overnight. After completion, the reaction was quenched with H 2 O (20 mL) and the aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with saturated NaCl solution (100 mL), dried over MgSO 4 , filtered, and concentrated under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of PE/EtOAc from 100/0 to 50/50 to afford compound 68 (1.78 g, 82%) as a white solid. Rf (CH2Cl2/acetone 70/30) 0.91. Mp: 183 - 185 °C. 1H NMR (400 MHz, DMSO-de) 88.91 (s, 1H, CH), 8.21 (s, 1H, CH), 8.07 (d, J = 8.4 Hz, 2H, 2 x CH), 7.47 (d, J = 8.2 Hz, 2H, 2 x CH), 6.11 - 5.96 (m, 1H, CH), 4.16 - 4.02 (m, 2H, CH2), 3.58 (t, J = 5.7 Hz, 2H, CH2), 2.55 - 2.48 (m, 2H, CH2), 2.36 (s, 3H, CH3), 1.43 (s, 9H, 3 x CH3). HRMS (EI-MS) m/z calcd. for C23H26 IN 4O4S [M+H]+: 581.0714, found: 581.0712.

4-(5-cyclopropyl-7-tosyl-7-pyrrolo[2,3-d]pyrimidin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester (69)

A microwave vial was charged with a magnetic stir bar, compound 68 (0.70 g, 1.21 mmol), cyclopropylboronic acid (0.26 g, 3.05 mmol, 2.5 equiv.), K PO (0.90 g, 4.24 mmol, 3.5 equiv.), P(Cy) (68 mg, 0.24 mmol, 0.2 equiv.), toluene (15 mL), and H O (1.5 mL)). The solution was degassed with argon for 15 min with stirring. Pd(OAc) (27 mg, 0.12 mmol, 0.1 equiv.) was added to the solution, the tube was sealed, and the reaction mixture was heated under microwave irradiation at 140 °C for 1 h. After cooling, cyclopropylboronic acid (0.10 g, 1.21 mmol, 1.0 equiv.) was added again and the reaction mixture was stirred for 30 min under microwave irradiation at 140 °C. Upon completion, H2O (30 mL) was added and the aqueous phase was extracted with CH2Cl2 (2 x 100 mL). The combined organic phases were washed with saturated NaCl solution (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Ch/acetone from 100/0 to 60/40 to afford compound69 (0.36 g, 60%) as a beige solid. Rf(CH2Ch/acetone 70/30) 0.90. Mp: degradation 90 °C. 1H NMR (400 MHz, MeOD-d4) 88.77 (s, 1H, CH), 8.03 (d, J = 8.4 Hz, 2H, 2 x CH), 7.55 (d, J= 1.3 Hz, 1H, CH), 7.37 (d, J= 8.1 Hz, 2H, 2 x CH), 6.20 - 6.05 (m, 1H, CH), 4.18 - 4.06 (m, 2H, CH2), 3.68 (t, J = 5.6 Hz, 2H, CH2), 2.65 - 2.57 (m, 2H, CH2), 2.37 (s, 3H, CH3), 1.85 - 1.75 (m, 1H, CH), 1.48 (s, 9H, 3 x CH3), 0.99 -0.83 (m, 2H, CH2), 0.72 - 0.61 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for C26H31N4O4S [M+H]+: 495.2061, found: 495.2058.

5-cyclopropyl-4-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (70)

To a solution of 69 (0.30 g, 0.61 mmol) in THF/H 2 O (12 mL, 5:1) was added KOH (0.31 g, 5.46 mmol, 9.0 equiv.). The reaction mixture was heated under reflux for 24 h. After cooling, the solution was extracted with CH 2 Cb (2 × 50 mL), and the combined organic layers were washed with saturated NaCl solution (30 mL), dried over MgSO 4 , filtered, and concentrated under reduced pressure. The residue was taken up in CH 2 Cl 2 (20 mL), the solution was cooled to 0 °C, and TFA (1.6 mL, 21.35 mmol, 35.0 equiv.) was added. The mixture was stirred for 2 h at room temperature. Excess TFA was removed under reduced pressure. The residue was suspended in CH2Cl2 (10 mL) and 2 M aqueous NaOH solution (3 mL) was added. The mixture was stirred for 30 min and extracted with CH2Cl2 (30 mL). The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to afford 70 (125 mg, 85%) as a white solid. Mp: 184 - 186 °C. 1H NMR (400 MHz, MeOD-d4) 88.60 (s, 1H, CH), 7.13 (d, J= 1.1 Hz, 1H, CH), 6.25 - 6.15 (m, 1H, CH), 3.58 - 3.51 (m, 2H, CH2), 3.14 (t, J = 5.7 Hz, 2H, CH2), 2.68 - 2.58 (m, 2H, CH2), 1.99 - 1.86 (m, 1H, CH), 0.94 - 0.84 (m, 2H, CH2), 0.66 - 0.57 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for C14H17N4 [M+H]+: 241.1448, found: 241.1447.

Example 39: 4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-W-(3-fluorophenyl)-5,6-dihydropyridin-1(2H)-carboxamide (71)

The reaction was carried out as described in the general procedure by using amine 70 (50 mg, 0.21 mmol) in 3-fluorophenyl isocyanate (26 µl, 0.23 mmol, 1.1 equiv.) in anhydrous CH 2 Cl 2 (5 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Cl 2 /acetone from 90/10 to 30/70 to provide compound 71 (44 mg, 56%) as a white solid. Rf (CH 2 Ch /acetone 50/50) 0.28. Mp: 149 - 151 °C. 1H NMR (250 MHz, MeOD-d4) 88.63 (s, 1H, CH), 7.41 -7.12 (m, 4H, 4 x CH), 6.81 - 6.67 (m, 1H, CH), 6.29 - 6.17 (m, 1H, CH), 4.36 - 4.21 (m, 2H, CH2), 3.85 (t, J= 5.6 Hz, 2H, CH2), 2.86 - 2.70 (m, 2H, CH2), 1.95 - 1.77 (m, 1H, CH), 0.99 - 0.77 (m, 2H, CH2), 0.67 - 0.51 (m, 2H, CH2). 19F NMR (235 MHz, MeOD-d4) 8 -114.87 - -115.04 (m). HRMS (EI-MS) m/z calcd. for C21H21FN5O [M+H]+: 378.1725, found: 378.1724.

Example 40: W-(3-chlorophenyl)-4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,6-dihydropyridine-1(2H)-carboxamide (72)

The reaction was carried out as described in the general procedure by using amine 70 (50 mg, 0.21 mmol) in anhydrous 3-chlorophenyl isocyanate (28 µl, 0.23 mmol, 1.1 equiv.) CH 2 Cl 2 (5 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Cl 2 /acetone from 90/10 to 30/70 to provide compound 72 (55 mg, 67%) as a white solid. Rf (CH 2 Ch /acetone 50/50) 0.28. Mp: 174 - 176 °C. 1H NMR (400 MHz, MeOD-d4) 8 8.63 (s, 1H, CH), 7.55 (t, J = 2.1 Hz, 1H, CH), 7.31 (d, J = 8.2 Hz, 1H, CH), 7.24 (t, J = 8.0 Hz, 1H, CH), 7.16 (s, 1H, CH), 7.01 (d, J = 7.2 Hz, 1H, CH), 6.25 - 6.19 (m, 1H, CH), 4.36 - 4.23 (m, 2H, CH2), 3.85 (t, J = 5.6 Hz, 2H, CH2), 2.84 - 2.71 (m, 2H, CH2), 1.93 - 1.77 (m, 1H, CH), 0.90 - 0.83 (m, 2H, CH2), 0.64 - 0.57 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for C21H21ClNsO [M+H]+: 394.1429, found: 394.1426.

Example 41: W-(3-bromophenyl)-4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,6-dihydropyridine-1(2H)-carboxamide (73)

The reaction was carried out as described in the general procedure by using amine 70 (50 mg, 0.21 mmol) in anhydrous 3-bromophenyl isocyanate (29 µl, 0.23 mmol, 1.1 equiv.) CH 2 Cl 2 (5 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Cl 2 /acetone from 90/10 to 30/70 to provide compound 73 (46 mg, 50%) as a white solid. Rf (CH 2 Ch /acetone 50/50) 0.28. Mp: 179 - 181 °C. 1H NMR (250 MHz, MeOD-d4) 88.63 (s, 1H, CH), 7.74 -7.66 (m, 1H, CH), 7.40 - 7.32 (m, 1H, CH), 7.23 - 7.11 (m, 3H, CH 2 x CH), 6.25 - 6.19 (m, 1H, CH), 4.34 - 4.23 (m, 2H, CH2), 3.85 (t, J = 5.6 Hz, 2H, CH2), 2.85 - 2.70 (m, 2H, CH2), 1.95 - 1.78 (m, 1H, CH), 0.94 - 0.78 (m, 2H, CH2), 0.67 - 0.54 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for C21H21BrNsO [M+H]+: 438.0924, found: 438.0922.

Example 42: 4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(3-phenylphenyl)-3,6-dihydropyridine-1(2H)-carboxamide ( 74)

The reaction was carried out as described in the general procedureHwith 1,1'-biphenyl]-3-amine (31 pl, 0.25 mmol) and amine70.HCl (37 mg, 0.12 mmol, 1.2 equiv.) in anhydrous THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Ch/acetone from 100/0 to 40/60 to give the desired compound74 (25 mg, 48%) as a yellow solid. Rf (CH2Cfc/acetone 40/60) 0.3. Mp: degradation 145 °C. 1H NMR (400 MHz, DMSO-de) 811.86 (s, 1H, NH), 8.73 - 8.57 (m, 2H, NH CH), 7.82 (s, 1H, CH), 7.62 (d,J =7.6 Hz, 2H, 2 x CH), 7.54 (d,J =8.0 Hz, 1H, CH), 7.47 (t,J =7.5 Hz, 2H, 2 x CH), 7.35 (q, J = 7.8 Hz, 2H, 2 x CH), 7.27 - 7.22 (m, 2H, 2 x CH), 6.29 (s, 1H, CH), 4.25 (s, 2H, CH2), 3.77 (t, J = 5.5 Hz, 2H, CH2), 2.72 (s, 2H, CH2), 1.90 - 1.78 (m, 1H, CH), 0.85 - 0.78 (m, 2H, CH2), 0.64 - 0.57 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for C27H26N5 O[M+H]+: 436.2132, found: 436.2130.

Example 43: [3-[[4-(5-c¡cloprop¡l-7H-pyrrolo[2,3-d]p¡rmád¡n-4) N,W-dimethylcarbamate -¡l)-3,6-d¡hydro¡r¡d¡n-1 (2H)-carbonyl]amino]phenyl (75)

The reaction was carried out as described in the general procedureHwith 3-aminophenyl dimethylcarbamate (18 mg, 0.10 mmol) and amino70.HCl (38 mg, 0.12 mmol, 1.2 equiv.) in anhydrous THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Cl2/acetone from 100/0 to 25/75 to give the desired compound75 (35 mg, 64%) as a white solid. Rf(CH2Ch/acetone 20/80) 0.28. Mp: degradation 132 °C. 1H NMR (400 MHz, DMSO-de) 811.83 (s, 1H, NH), 8.67 (s, 1H, CH), 8.64 (s, 1H, NH), 7.35 (t, J = 2.1 Hz, 1H, CH), 7.31 (d, J = 2.1, Hz, 1H, CH), 7.28 - 7.19 (m, 2H, 2 * CH), 6.71 - 6.66 (m, 1H, CH), 6.27 (s, 1H, CH), 4.24 - 4.19 (m, 2H, CH2), 3.74 (t, J = 5.6 Hz, 2H, CH2), 3.03 (s, 3H, NCH3), 2.90 (s, 3H, NCH3), 2.73 - 2.64 (m, 2H, CH2), 1.88 - 1.77 (m, 1H, CH), 0.84 - 0.76 (m, 2H, CH2), 0.63 - 0.52 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for C24H27N6O3 [M+H]+: 447.2139, found: 447.2137.

Example_____ 44: 4-(5-c¡cloprop¡l-7H-p¡rrolo[2,3-d]p¡r¡m¡d¡n-4-¡l)-W-[3-(2- methoxy¡phen¡l)phen¡l]-3,6di¡hydro¡r¡d¡n-1(2H)-carboxamide (76)

The reaction was carried out as described in the general procedureHwith 2'-methoxy-[1,1'-phenyl]-3-amine (25 mg, 0.12 mmol) and amine70.HCl (48 mg, 0.15 mmol, 1.2 equiv.) in anhydrous THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Cl2/acetone from 100/0 to 30/70 to give the desired compound76 (35 mg, 58%) as a white solid. Rf (CH2Ch/acetone 30/70) 0.43. Mp: degradation 140 °C. 1H NMR (400 MHz, DMSO-de) 811.95 (s, 1H, NH), 8.68 (s, 1H, CH), 8.61 (s, 1H, NH), 7.59 (s, 1H, CH), 7.48 (d, J = 8.2 Hz, 1H, CH), 7.33 (t, J = 8.2 Hz, 1H, CH), 7.31 -7.21 (m, 3H, 3xCH), 7.10 (d, J = 8.3 Hz, 1H, CH), 7.08 - 6.98 (m, 2H, 2 x CH), 6.30 (s, 1H, CH), 4.24 (s, 2H, CH2), 3.76 (s, 5H, OCH3 CH2), 2.71 (s, 2H, CH2), 1.84 (m, 1H, CH), 0.85 - 0.78 (m, 2H, CH2), 0.64 - 0.57 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for C28H28N5O2 [M+H]+: 466.2238, found: 466.2234.

Example____ 45: 4-(5-c¡c¡cloprop¡l-7H-p¡rrolo[2,3-d]p¡r¡m¡d¡n-4-¡l)-W-[3-(3- methoxy¡phen¡l)phen¡l]-3,6di¡hydro¡r¡d¡n-1(2H)-carboxamide (77)

The reaction was carried out as described in the general procedureHwith 3'-methoxy-[1,1'-benzyl]-3-amine (25 mg, 0.12 mmol) and amine70.HCl (48 mg, 0.15 mmol, 1.2 equiv.) in anhydrous THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Cl2/acetone from 100/0 to 40/60 to give the desired compound77 (40 mg, 67%) as a white solid. Rf (CH2Ch/acetone 30/70) 0.67. Mp: degradation 199 °C. 1H NMR (400 MHz, DMSO-de) 811.86 (s, 1H, NH), 8.66 (s, 2H, NH CH), 7.80 (s, 1H, CH), 7.55 (d, J = 8.1 Hz, 1H, CH), 7.38 (t, J = 7.9 Hz, 1H, CH), 7.33 (t, J = 7.9 Hz, 1H, CH), 7.29 - 7.22 (m, 2H, 2 x CH), 7.18 (d, J = 7.7 Hz, 1H, CH), 7.16 - 7.11 (m, 1H, CH), 6.94 (dd, J = 8.2, 2.6 Hz, 1H, CH), 6.29 (s, 1H, CH), 4.30 - 4.20 (m, 2H, CH2), 3.82 (s, 3H, OCH3), 3.77 (t, J = 5.7 Hz, 2H, CH2), 2.72 (s, 2H, CH2), 1.91 - 1.78 (m, 1H, CH), 0.86 - 0.76 (m, 2H, CH2), 0.65 - 0.52 (m, 2H, CH2). HRMS (EI-MS): m/z calcd. for C28H28N5O2 [M+H]+: 466.2238, found: 466.2235.

Example____ 46: 4-(5-c¡c¡cloprop¡l-7H-p¡rrolo[2,3-d]p¡r¡m¡d¡n-4-¡l)-N-[3-(4- methoxy¡phen¡l)phen¡l]-3,6d¡hydrop¡r¡d¡n-1(2H)-carboxamide (78)

The reaction was carried out as described in the general procedureHwith 4'-methoxy-[1,1'-benzyl]-3-amine (25 mg, 0.12 mmol) and amine70.HCl (48 mg, 0.15 mmol, 1.2 equiv.) in anhydrous THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Cl2/acetone from 100/0 to 40/60 to give the desired compound78 (40 mg, 67%) as a clear beige solid. Rf (CH2Ch/acetone 30/70) 0.4. Mp: degradation 149 °C. 1H NMR (400 MHz, DMSO-de) 8 11.89 (s, 1H, NH), 8.67 (s, 1H, CH), 8.64 (s, 1H, NH), 7.77 (s, 1H, CH), 7.55 (d, J = 8.6 Hz, 2H, 2 x CH), 7.48 (d, J = 8.1 Hz, 1H, CH), 7.33 - 7.24 (m, 2H, 2 x CH), 7.19 (d, J = 7.6 Hz, 1H, CH), 7.03 (d, J = 8.5 Hz, 2H, 2 x CH), 6.30 (s, 1H, CH), 4.31 - 4.19 (m, 2H, CH2), 3.84 - 3.71 (m, 5H, OCH3 CH2), 2.72 (s, 2H, CH2), 1.90 - 1.78 (m, 1H, CH), 0.82 (d, J = 7.0 Hz, 2H, CH2), 0.61 (d, J = 4.2 Hz, 2H, CH2). HRMS (EI-MS) m/z calcd. for C28H28N5O2 [M+H]+: 466.2238, found: 466.2234.

Example 47: 4-(5-c¡c¡cloprop¡l-7H-pyrrolo[2,3-d]p¡r¡m¡d¡n-4-¡l)-N-(3-phenoxy¡phen ¡l)-3,6-di¡hydro¡r¡d¡n-1(2H)-carboxamide (79)

The reaction was carried out as described in the general procedureGwith amine70.HCl (48 mg, 0.15 mmol) in CH2Cl2 (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Cl2/acetone from 80/20 to 70/30 to give the desired compound79 (35 mg, 58%) as a white solid. Rf (CH2Ch/acetone 30/70) 0.52. Mp: degradation 124 °C. 1H NMR (400 MHz, DMSO-de) 811.89 (s, 1H, NH), 8.66 (s, 2H, CH NH), 7.39 (t, J = 8.0 Hz, 2H, 2 x CH), 7.33 - 7.20 (m, 4H, 4xCH), 7.13 (t,J = 7.4 Hz,1H, CH), 7.01 (d,J =7.7 Hz, 2H, 2 x CH), 6.64 - 6.57 (m, 1H, CH), 6.26 (s, 1H, CH), 4.22 -4.17 (m, 2H, CH2), 3.72 (t, J = 5.5 Hz, 2H, CH2), 2.68 (m, 2H, CH2), 1.87 - 1.74 (m, 1H, CH), 0.85 - 0.72 (m, 2H, CH2), 0.64 - 0.53 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for C27H26N5O2 [M+H]+: 452.2081, found: 452.2076.

3-(1H-pyrrole-1-yl)aniline (80)

An oven-dried microwave vial was charged with a magnetic stir bar, Cul (29 mg, 0.15 mmol, 0.05 equiv.), KPO (1.33 g, 6.26 mmol, 2.1 equiv.), and 1,10-phenanthroline (107 mg, 0.60 mmol, 0.2 equiv.). The tube was then evacuated and filled with argon. The evacuation/filling sequence was repeated two additional times. Under a counterflow of argon, 3-iodoaniline (0.43 mL, 3.58 mmol, 1.2 equiv.), pyrrole (0.21 mL, 2.98 mmol), and degassed 1,4-dioxane (1.5 mL) were added via syringe. The tube was placed in a preheated oil bath at 110 °C and the solution was stirred vigorously for 24 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (2-3 mL), filtered through a plug of Celite and eluted with EtOAc. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica gel using a gradient solvent system of PE/EtOAc from 90/10 to 80/20 to afford compound 80 (0.41 g, 87%) as a brown solid. 1H NMR (250 MHz, CDCla) 87.22 (t, J = 8.0 Hz, 1H, H), 7.11 (t, J = 2.2 Hz, 2H, 2 x CH), 6.83 (ddd, J = 8.0 Hz, J = 2.1 Hz, J = 0.9 Hz, 1H, CH), 6.71 (t, J = 2.2 Hz, 1H, CH), 6.57 (ddd, J = 8.0 Hz, J = 2.3 Hz, J =0.9 Hz, 1H, CH), 6.40 (t, J = 2.2 Hz, 2H, 2 x CH), 3.76 (brs, 2H, NH2). Tetrahedron 2011, 67, 898-903.

Example 48: 4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-W-(3-pyrrole-1-ylphenyl)-3,6-dihydropyridin-1(2H)- carboxamide (81)

The reaction was carried out as described in the general procedureHwith 3-(1H-pyrrol-1-yl)aniline 80 (22 mg, 0.14 mmol) and amine70.HCl (53 mg, 0.16 mmol, 1.2 equiv.) in anhydrous THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Cl2/acetone from 100/0 to 50/50 to give the desired compound81 (42 mg, 70%) as a white solid. Rf(CH2Ch/acetone 70/30) 0.25. Mp: degradation 140 °C. 1H NMR (400 MHz, DMSO-de) 811.84 (s, 1H, NH), 8.72 (s, 1H, NH), 8.65 (s, 1H, CH), 7.74 (s, 1H, CH), 7.41 (d, J = 7.9 Hz, 1H, CH), 7.32 (t, J = 8.0 Hz, 1H, CH), 7.27 -7.21 (m, 3H, 3 x CH), 7.13 (d, J = 7.7 Hz, 1H, CH), 6.43 - 6.07 (m, 3H, 3 x CH), 4.31 - 4.16 (m, 2H, CH2), 3.77 (t, J = 5.4 Hz, 2H, CH2), 2.77 - 2.68 (m, 2H, CH2), 1.91 - 1.77 (m, 1H, CH), 0.86 - 0.75 (m, 2H, CH2), 0.66 - 0.53 (m, 2H, CH2).

HRMS (EI-MS) m/z calcd. for C25H24N6 O[M+H]+: 425.2084, found: 425.2084.

Example_____ 49: 4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-[3-(3-methoxyphenyl)phenyl]-3,6dihydropyridine-1(2H)-carboxamide (82)

The reaction was carried out as described in the general procedureH with 3-(3-methoxyphenoxy)aniline (22 mg, 0.11 mmol) and amine70.HCl (47 mg, 0.15 mmol, 1.2 equiv.) in anhydrous THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Cl2/acetone from 100/0 to 40/60 to give the desired compound82 (32 mg, 53%) as a white solid. Rf (CH2Ch/acetone 40/60) 0.35. Mp: degradation 186 °C. 1H NMR (400 MHz, DMSO-de) 811.83 (s, 1H, NH), 8.69 - 8.61 (m, 2H, NH CH), 7.39 - 7.07 (m, 5H, 5xCH), 6.71 (dd, J = 8.2, J = 2.4 Hz, 1H, CH), 6.62 (d, J = 7.9 Hz, 1H, CH), 6.58 (t, J = 2.3 Hz, 1H, CH), 6.57 - 6.53 (m, 1H, CH), 6.25 (s, 1H, CH), 4.22 - 4.17 (m, 2H, CH2), 3.80 - 3.64 (m, 5H, OCH3 CH2), 2.68 (s, 2H, CH2), 1.88 - 1.76 (m, 1H, CH), 0.86 - 0.73 (m, 2H, CH2), 0.65 - 0.52 (m, 2H, CH2HRMS (ElMS) m/z calcd. for C28H2sN5O3[M+H]+: 482.2187, found: 482.2186.

Example 50: N-cyclohexyl-4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (83)

The reaction was carried out as described in the general procedureH with cyclohexylamine (13 mg, 0.11 mmol) and amine70.HCl (51 mg, 0.16 mmol, 1.2 equiv.) in anhydrous THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Ch/acetone from 100/0 to 40/60 to give the desired compound83 (35 mg, 60%) as a white solid. Rf (CH2Ch/acetone 30/70) 0.27. Mp: 201 °C. 1H NMR (400 MHz, DMSO-de) 811.82 (s, 1H, NH), 8.62 (s, 1H, CH), 7.23 (s, 1H, CH), 6.20 (m, 2H, NH CH), 4.03 (s, 2H, CH2), 3.57 (t, J = 5.5 Hz, 2H, CH2), 3.51 - 3.41 (m, 1H, CH), 2.59 (s, 2H, CH2), 1.84 - 1.63 (m, 5H, CH CH2), 1.57 (d, J = 11.9 Hz, 1H, CH2), 1.33 - 0.99 (m, 5H, 2 x CH2, CH), 0.85 - 0.74 (m, 2H, CH2), 0.63 - 0.53 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for C21H28N5 O[M+H]+: 366.2290, found: 366.2288.

Family 5.

Derivatives of 2,3-dimethylpyrrolopyrimidine with an unsubstituted hydropyridine.

6-[(2E)-2-(1-methylpropylidene)hydrazino]pyrimidin-4-ol (84)

The reaction was carried out as described in the general procedure A with 4-hydroxy-6-hydrazinyl pyrimidine (2.0 g, 15.9 mmol). The desired product 84 (2.7 g, 95%) was obtained as a white solid. Rf (acetone) 0.31. Mp: degradation 225 °C. 1H NMR (400 MHz, DMSO-*) 5 11.64 (s, 1H, NH), 9.40 (s, 1H, OH), 7.90 (s, 1H, CH), 5.55 (s, 1H, CH), 2.25 (q, J = 7.4 Hz, 2H, CH2), 1.88 (s, 3H, CH3), 1.04 (t, J = 7.4 Hz, 3H, CH3). HRMS (EI-MS) m/z calcd. for C8H13N4 O[M+H]+: 181.1084, found: 181.1083.

5,dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ol (85)

The reaction was carried out as described in the general procedureKusando84(400 mg, 2.21 mmol). The desired product85(300 mg, 92%) was obtained as a light brown solid. Rf (CH2Cl2/acetone 20/80) 0.35. Mp: degradation > 266 °C. 1H NMR (400 MHz, DMSO-ri?) 5 11.54 (s, 1H, OH), 11.38 (s, 1H, NH), 7.67 (s, 1H, CH), 2.18 (s, 3H, CH3), 2.15 (s, 3H, CH3). HRMS (EI-MS) m/z calcd. for C8H10N3 O[M+H]+: 164.0818, found: 164.0814.

4-chloro-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidine (86)

The reaction was carried out as described in general procedure C using85(400 mg, 2.45 mmol). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Cl2/acetone from 100/0 to 70/30 to afford compound86(267 mg, 60%) as a white solid. Rf (CH2Cb/acetone 70/30) 0.49. Mp: degradation 232 °C. 1H NMR (400 MHz, DMSO-*) 512.13 (s, 1H, NH), 8.40 (s, 1H, CH), 2.32 (s, 3H, CH3), 2.30 (s, 3H, CH3). HRMS (EI-MS) m/z calcd. for C8H9ClN3[M+H]+: 182.0480, found: 182.0475.

4-(5,6-dimet¡l-7H-pyrrolo[2,3-d]p¡r¡m¡din-4-¡l)-3,6-dihydro Fert-butyl-2H-pyridin-1-carboxylate (87)

The reaction was carried out as described in the general procedure Dusando 86 (109 mg, 0.6 mmol). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Cl / acetone from 100/0 to 50/50 to provide compound 87 (58 mg, 30%) as a white solid. R f (CH 2 Cl 2 / acetone 60/40): 0.26. Mp: degradation 162 °C. 1H NMR (250 MHz, CDCla) 611.07 (s, 1H, NH), 8.72 (s, 1H, CH), 5.92 (s, 1H, CH), 4.15 (s, 2H, CH2), 3.71 (t, J = 5.6 Hz, 2H, CH2), 2.76 - 2.65 (m, 2H, CH2), 2.44 (s, 3H, CH3), 2.18 (s, 3H, CH3), 1.50 (s, 9H, CH3). HRMS (EI-MS) m/z calcd. for C1sH25N4O2[M+H]+: 329.1972, found: 329.1973.

5,6-Dimethyl-4-(1,2,3,6-tetrahydrochloride-4-l)-7H-pyrrole[2,3] hydrochloride -d]p¡r¡m¡d¡na (88)

The reaction was carried out as described in the general procedureJusando87(350 mg, 1.07 mmol). The desired product88(345 mg, qty) was obtained as a yellow solid (HCl salt). Mp: degradation > 266 °C. 1H NMR (400 MHz, DMSO-de) 613.27 (s, 1H, NH), 9.95 (s, 2H, NH2 (salt)), 8.92 (s, 1H, CH), 6.28 (s, 1H, CH), 3.86 (s, 2H, CH2), 3.35 (s, 2H, CH2), 2.92 (s, 2H, CH2), 2.43 (s, 3H, CH3), 2.21 (s, 3H, CH3). HRMS (EI-MS) m/z calcd. for C1aH1/N4[M+H]+: 229.1448, found: 229.1446.

Example 51: W-(3-bromophen¡l)-4-(5,6-dimet¡l-7H-pyrrolo[2,3-d]p¡r¡m¡d¡n-4- l)-3,6-dihydro-2H-pyridine-1-carboxamide (89)

The reaction was carried out as described in the general procedure Gusando 88 (42 mg, 0.14 mmol). The crude mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Cl 2 / acetone from 100/0 to 50/50 to provide compound 89 (45 mg, 75%) as a white solid. R f (CH 2 Ch / acetone 50/50): 0.25. Mp: degradation > 266 °C. 1H NMR (400 MHz, DMSO-de) 6 11.76 (s, 1H, NH), 8.75 (s, 1H, NH), 8.55 (s, 1H, CH), 7.83 (s, 1H, CH), 7.50 (d, J = 8.6 Hz, 1H, CH), 7.21 (t, J = 8.1 Hz, 1H, CH), 7.12 (d, J = 8.0 Hz, 1H, CH), 5.97 (s, 1H, CH), 4.21 (s, 2H, CH2), 3.73 (t, J = 5.6 Hz, 2H, CH2), 2.66 (s, 2H, CH2), 2.33 (s, 3H, CH3), 2.13 (s, 3H, CH3). HRMS (EI-MS) m/z calcd. for C20H21BrNaO [M+H]+: 426.0924, found: 426.0919.

Example 52: 4-(5,6-d¡met¡l-7H-pyrrolo[2,3-d]p¡r¡m¡d¡n-4-¡l)-N-phen¡l- 3,6-dihydro-2H-pyridin-1-carboxamide (90)

The reaction was carried out as described in the general procedure Gusando 88 (52 mg, 0.17 mmol). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch / acetone from 100/0 to 50/50 to provide compound 90 (43 mg, 72%) as a white solid. R f (CH 2 Ch / acetone 70/30) 0.48. Mp: degradation > 266 °C. 1H NMR (400 MHz, DMSO-de) 6 11.77 (s, 1H, NH), 8.59 - 8.53 (m, 2H, NH CH), 7.50 (d, J = 8.0 Hz, 2H, CH), 7.24 (t, J = 7.7 Hz, 2H, CH), 6.94 (t, J = 7.3 Hz, 1H, CH), 5.98 (s, 1H, CH), 4.21 (s, 2H, CH2), 3.73 (t, J = 5.5 Hz, 2H, CH2), 2.66 (s, 2H, CH2), 2.33 (s, 3H, CH3), 2.14 (s, 3H, CH3). HRMS (EI-MS) m/z calcd. for C20H22N5 O[M+H]+: 348.1819, found: 348.1821.

Example 53: 4-(5,6-d¡ethyl¡l-7H-pyrrolo[2,3-d]p¡r¡m¡d¡n-4-¡l)-N-(3-methox phenyl)-3,6-dihydro-2H-pyridin-1-carboxamide (91)

The reaction was carried out as described in the general procedure Gusando 88 (48 mg, 0.16 mmol). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch / acetone from 100/0 to 40/60 to provide compound 91 (33 mg, 55%) as a white solid. R f (CH 2 Ch / acetone 30/70) 0.36. Mp: degradation > 266 °C. 1H NMR (400 MHz, DMSO-de) 6 11.80 (s, 1H, NH), 8.60 - 8.53 (m, 2H, NH CH), 7.20 (s, 1H, CH), 7.17 - 7.06 (m, 2H, CH), 6.52 (d, J = 7.5 Hz, 1H, CH), 5.98 (s, 1H, CH), 4.20 (s, 2H, CH2), 3.72 (s, 5H, CH3 CH2), 2.66 (s, 2H, CH2), 2.33 (s, 3H, CH3), 2.13 (s, 3H, CH3). HRMS (EI-MS) m/z calcd. for C21H24NaO2[M+H]+: 378.1925, found: 378.1922.

Example 54: 4-(5,6-d¡ethyl¡l-7H-pyrrolo[2,3-d]p¡r¡m¡d¡n-4-¡l)-N-(3-phen l-phenyl)-3,6-dihydro-2H-pyridin-1-carboxamide (92)

The reaction was carried out as described in the general procedureHwith 1,1'-phenyl]-3-amine (16 mg, 0.14 mmol) and88 (51 mg, 0.17 mmol, 1.2 equiv.) in THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a 70/30 CH2Ch/acetone solvent system to give compound92 (29 mg, 48%) as a white solid. Rf (CH2Ch/acetone 50/50) 0.35. Mp: degradation 144 °C. 1H NMR (400 MHz, DMSO-de) 611.78 (s, 1H, NH), 8.68 (s, 1H, NH), 8.57 (s, 1H, CH), 7.83 (s, 1H, CH), 7.62 (d, J = 7.6 Hz, 2H, CH), 7.55 (d, J = 8.0 Hz, 1H, CH), 7.47 (t, J = 7.6 Hz, 2H, CH), 7.35 (q, J = 7.8 Hz, 2H, CH), 7.24 (d, J = 7.7 Hz, 1H, CH), 5.99 (s, 1H, CH), 4.24 (s, 2H, CH2), 3.76 (t, J = 4.9 Hz, 2H, CH2), 2.68 (s, 2H, CH2), 2.33 (s, 3H, CH3), 2.14 (s, 3H, CH3). HRMS (EI-MS) m/z calcd. for C23H25N5 O[M+H]+: 424.2132, found: 424.2128.

Example 55: 4-(5,6-d¡met¡l-7H-pyrrolo[2,3-d]p¡r¡m¡d¡n-4-¡l)-W-[3-( 3-methoxy¡phen¡l)phen¡l]-3,6d¡hydrop¡r¡d¡n-1(2H)-carboxamide (93)

The reaction was carried out as described in the general procedure using 4'-methoxy-[1,1'-phenyl]-3-amine (26 mg, 0.13 mmol) and the amine salt 88 (48 mg, 0.16 mmol, 1.2 equiv.) in THF (4 mL). The crude mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch /acetone from 100/0 to 40/60 to give 93 (30 mg, 50%) as a white solid. Rf (CH 2 Ch /acetone 30/70) 0.53. Mp: degradation 248 °C.<1>H NMR (400 MHz, DMSO-d?) 511.77 (s, 1H, NH), 8.64 (s, 1H, NH), 8.56 (s, 1H, CH), 7.77 (s, 1H, CH), 7.55 (d, J = 8.4 Hz, 2H, CH), 7.49 (d, J = 7.9 Hz, 1H, CH), 7.30 (t, J = 7.8 Hz, 1H, CH), 7.19 (d, J = 7.7 Hz, 1H, CH), 7.03 (d, J = 8.3 Hz, 2H, CH), 5.99 (s, 1H, CH), 4.23 (s, 2H, CH<2>), 3.80 (s, 3H, CH<3>), 3.79 - 3.71 (m, 2H, CH<2>), 2.67 (s, 2H, CH<2>), 2.33 (s, 3H, CH<3>), 2.14 (s, 3H, CH<3>). HRMS (EI-MS) m/z calcd. for C<27>H<28>N<5>O<2>[M+H]<+>: 454.2238, found: 454.2238.

Example 56: [3-[[4-(5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydro-2H-pyridine-W,W-dimethylcarbamate 1-carbonyl]amino]phenyl (94)

The reaction was carried out as described in the general procedure using 3-aminophenyldimethyl carbamate (45 mg, 0.25 mmol) and the amine salt 88 (50 mg, 0.17 mmol, 1.2 equiv.) in THF (4 mL). The crude mixture was purified by silica gel column chromatography using a gradient solvent system of CH<2>Cl<2>/acetone from 100/0 to 50/50 to provide 94 (35 mg, 58%) as a pale yellow solid. Rf(CH<2>Cl<2>/acetone 30/70): 0.41. Mp: degradation 142 °C.<1>H NMR (400 MHz, DMSO-d<6>) 5 11.81 (s, 1H, NH), 8.69 (s, 1H, NH), 8.57 (s, 1H, CH), 7.38 (s, 1H, CH), 7.32 (d, J = 8.2 Hz, 1H, CH), 7.22 (t, J = 8.1 Hz, 1H, CH), 6.69 (d, J = 7.4 Hz, 1H, CH), 5.99 (s, 1H, CH), 4.21 (s, 2H, CH<2>), 3.73 (t, J = 5.4 Hz, 2H, CH<2>), 3.04 (s, 3H, CH<3>), 2.91 (s, 3H, CH<3>), 2.65 (s, 2H, CH<2>), 2.33 (s, 3H, CH<3>), 2.13 (s, 3H, CH<3>). HRMS (EI-MS) m/z calcd. for C<23>H<27>N<6>O<3>[M+H]<+>: 435.2136, found: 435.2139.

Family 6.

Tricyclic derivatives with an alkyl ring in the 2 and 3 positions of the pyrrolopyrimidine and an unsubstituted hydropyridine.

107-109 110-137

6-(2-cyclopentylidenehydrazinyl)pyrimidin-4-ol (95)

The reaction was carried out as described in the general procedure using 4-hydroxy-6-hydrazinylpyrimidine (1.0 g, 7.93 mmol) and cyclopentanone (1.05 mL, 11.89 mmol, 1.5 equiv.) in EtOH (16 mL). The precipitate was filtered and washed with Et2O (2 x 20 mL) to provide compound95 (1.18 g, 77%) as a white solid.

Rf(CH2Cl2/acetone 50/50) 0.10. Mp: > 260 °C. 1H NMR (250 MHz, MeOD-d4) 87.91 (s, 1H, CH), 5.84 (s, 1H, CH), 2.52 - 2.27 (m, 4H, CH2 CH2), 1, 97 - 1.65 (m, 4H, CH2 CH2). HRMS (EI-MS) m/z calcd. for C9H13N4 O[M+H]+: 193.1084, found: 193.1085.

6-(2-cyclohexylidenhydrazinyl)pyrimidin-4-ol (96)

The reaction was carried out as described in the general procedure using 4-hydroxy-6-hydrazinylpyrimidine (1.0 g, 7.93 mmol) and cyclohexanone (1.16 mL, 11.89 mmol, 1.5 equiv.) in EtOH (16 mL). The precipitate was filtered and washed with Et2O (2 x 20 mL) to provide96(1.17 g, 72%) as a white solid. Rf (CH2Ch/acetone 50/50) 0.11. Mp: > 260 °C. 1H NMR (250 MHz, MeOD-d4) 87.90 (d, J = 0.8 Hz, 1H, CH), 5.86 (d, J = 0.8 Hz, 1H, CH), 2.49 - 2.39 (m, 2H, CH2), 2.39 - 2.31 (m, 2H, CH2), 1.80 - 1.59 (m, 6H, 3 x CH2). HRMS (EI-MS) m/z calcd. for C10H15N4 O[M+H]+: 207.1240, found: 207.1239.

6-(2-cycloheptylidenehydrazinyl)pyrimidin-4-ol (97)

The reaction was carried out as described in the general procedure using 4-hydroxy-6-hydrazinylpyrimidine (1.0 g, 7.93 mmol) and cycloheptanone (1.4 mL, 11.89 mmol, 1.5 equiv.) in EtOH (16 mL). The precipitate was filtered and washed with Et2O (2 x 20 mL) to give compound97 (1.3 g, 76%) as a beige solid. Rf (CH2Ch/acetone 50/50) 0.11. Mp: > 260 °C. 1H NMR (400 MHz, DMSO-de) 8 11.65 (brs, 1H, OH), 9.22 (s, 1H, NH), 7.89 (s, 1H, CH), 5.55 (s, 1H, CH), 2.48 - 2.44 (m, 2H, CH2), 2.44 - 2.40 (m, 2H, CH2), 1.68 - 1.60 (m, 2H, CH2), 1.59 - 1.45 (m, 6H, 3 x CH2). HRMS (EI-MS) m/z calcd. for C11H17N4 O[M+H]+: 221.1397, found: 221.1396.

5.6.7.8-tetrahydrocyclopenta[4,5]pyrrolo[2,3-d]pyrimidin-4-ol (98)

The reaction was carried out as described in the general procedure using hydrazone 95 (0.5 g, 2.60 mmol) in tetralin (10 mL). The precipitate was filtered and washed several times with PE (3 x 10 mL) and Et 2 O (10 mL) to afford compound 98 (0.39 g, 85%) as a gray solid. Rf (CH 2 Ch / MeOH / NH 4 OH 90/9/1) 0.33. Mp: > 260 °C. 1H NMR (250 MHz, DMSO-de) 811.66 (brs, 1H, OH), 11.59 (s, 1H, NH), 7.69 (s, 1H, CH), 2.79 - 2.64 (m, 4H, 2 x CH2), 2.42 - 2.26 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for C9H10N3 O[M+H]+: 176.0818, found: 176.0821.

6.7.8.9- tetrahydro-5H-pyrimido[4,5-b]indole-4-ol (99)

The reaction was carried out as described in the general procedure using hydrazone 96 (0.5 g, 2.42 mmol) in tetralin (10 mL). The precipitate was filtered and washed several times with PE (3 x 10 mL) and Et 2 O (10 mL) to afford compound 99 (0.41 g, 89%) as a beige solid. Rf (CH 2 Ch / MeOH / NH 4 OH 90/9/1) 0.35. Mp: > 260 °C. 1H NMR (400 MHz, DMSO-de) 8 11.56 (brs 1H, OH), 11.37 (s, 1H, NH), 7.68 (s, 1H, CH), 2.66 (t, J = 5.9 Hz, 2H, CH2), 2.55 (t, J = 6.0 Hz, 2H, CH2), 1.79 - 1.65 (m, 4H, 2 x CH2). HRMS (EI-MS) m/z calcd. for C10H12N3 O[M+H]+: 190.0975, found: 190.0975.

5,6,7,8,9,10-hexahydrocyclohepta[4,5]pyrrolo[2,3-d]pyrimidin-4-ol (100)

The reaction was carried out as described in the general procedure using hydrazone 97 (0.5 g, 2.27 mmol) in tetralin (10 mL). The precipitate was filtered and washed several times with PE (3 x 10 mL) and Et 2 O (10 mL) to afford compound 100 (0.41 g, 88%) as a beige solid. Rf (CH 2 Ch / MeOH / NH 4 OH 90/9/1) 0.34. Mp: > 260 °C. 1H NMR (250 MHz, DMSO-de) 811.53 (brs, 1H, OH), 11.40 (s, 1H, NH), 7.66 (s, 1H, CH), 3.01 - 2.83 (m, 2H, CH2), 2.74 - 2.61 (m, 2H, CH2), 1.83 - 1.72 (m, 2H, CH2), 1.66 - 1.52 (m, 4H, 2 x CH2). HRMS (EI-MS) m/z calcd. for C11H14N3 O[M+H]+: 204.1131, found: 204.1132.

4-chloro-5,6,7,8-tetrahydrocyclopenta[4,5]pyrrolo[2,3-d]pyrimidine (101)

The reaction was carried out as described in the general procedure using tricycle98 (1.0 g, 5.71 mmol) in POCla (40 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Ch/acetone from 100/0 to 70/30 to afford101 (0.83 g, 75%) as a white solid. Rf (CH2Ch/acetone 80/20) 0.31. Mp: degradation 239 °C. 1H NMR (250 MHz, DMSO-de) 812.31 (brs, 1H, NH), 8.42 (s, 1H, CH), 2.95 - 2.81 (m, 4H, 2 x CH2), 2.48 - 2.38 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for CgH9ClN3[M+H]+: 194.0480, found: 194.0480.

4-chloro-6,7,8,9-tetrahydro-5H-pyrimido[4,5-6]indole (102)

The reaction was carried out as described in the general procedure using tricycle99 (1.0 g, 5.28 mmol) in POCl3 (40 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Ch/acetone from 100/0 to 70/30 to afford compound102 (0.86 g, 78%) as a white solid. Rf (CH2Ch/acetone 80/20) 0.34. Mp: degradation 240 °C. 1H NMR (250 MHz, DMSO-de) 812.13 (s, 1H, NH), 8.41 (s, 1H, CH), 2.84 - 2.76 (m, 2H, CH2), 2.76 - 2.67 (m, 2H, CH2), 1.87 -1.73 (m, 4H, 2 x CH2). HRMS (EI-MS) m/z calcd. for C10HnClN3[M+H]+: 208.0636, found: 208.0637.

4-chloro-5,6,7,8,9,10-hexahydrocyclohepta[4,5]pyrrolo[2,3-d]pyrimidine (103)

The reaction was carried out as described in the general procedure by taking tricycle100 (1.0 g, 4.92 mmol) in POCl3 (35 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Ch/acetone from 100/0 to 70/30 to afford compound103 (0.81 g, 74%) as an off-white solid. Rf (CH2Ch/acetone 80/20) 0.36. Mp: 249 - 251 °C. 1H NMR (250 MHz, DMSO-de) 812.19 (s, 1H, NH), 8.39 (s, 1H, CH), 3.12 - 2.94 (m, 2H, CH2), 2.89 - 2.77 (m, 2H, CH2), 1.90 -1.74 (m, 2H, CH2), 1.74 - 1.59 (m, 4H, 2 x CH2). HRMS (EI-MS) m/z calcd. for CnH13ClN3 [M+H]+: 222.0793, found: 222.0792.

4-(5,6,7,8-tetrahydrocyclopenta[4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester (104)

The reaction was carried out as described in the general procedure using chlorinated tricycle 101 (0.35 g, 1.81 mmol) and W-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (0.62 g, 1.99 mmol, 1.1 equiv.) in THF (9 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch / acetone from 90/10 to 50/50 to provide compound 104 (0.54 g, 88%) as a white solid. Rf (CH 2 Ch / acetone 70/30) 0.23. Mp: 213 - 215 °C. 1H NMR (250 MHz, DMSO-de) 811.95 (s, 1H, NH), 8.55 (s, 1H, CH), 6.56 - 6.46 (m, 1H, CH), 4.15 - 4.04 (m, 2H, CH2), 3.56 (t, J = 5.7 Hz, 2H, CH2), 2.94 - 2.78 (m, 4H, 2 x CH2), 2.72 - 2.60 (m, 2H, CH2), 2.41 (p, J = 7.7 Hz, 2H, CH2), 1.44 (s, 9H, 3 x CH3). HRMS (EI-MS) m/z calcd. for C19H25N4O2 [M+H]+: 341.1972, found: 341.1970.

4-(6,7,8,9-tetrahydro-5H-pyrimido[4,5-6]indol-4-yl)-3,6-dihydropyridine-(2H)-carboxylate tert-butyl ester (105)

The reaction was carried out as described in the general procedure using chlorinated tricycle 102 (0.45 g, 2.17 mmol) and W-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (0.74 g, 2.38 mmol, 1.1 equiv.) in THF (9 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch / acetone from 90/10 to 50/50 to provide compound 105 (0.67 g, 87%) as a white solid. Rf (CH 2 Ch / acetone 70/30) 0.26. Mp: 214 - 216 °C. 1H NMR (250 MHz, DMSO-de) 811.73 (s, 1H, NH), 8.54 (s, 1H, CH), 6.07 - 5.95 (m, 1H, CH), 4.13 - 3.97 (m, 2H, CH2), 3.64 - 3.49 (m, 2H, CH2), 2.78 - 2.64 (m, 2H, CH2), 2.65 - 2.53 (m, 4H, 2 x CH2), 1.90 - 1.67 (m, 4H, 2 x CH2), 1.43 (s, 9H, 3 x CH3). HRMS (EI-MS) m/z calcd. for C20H27N4O2 [M+H]+: 355.2129, found: 355.2129.

4-(5,6,7,8,9,10-hexahydrocyclohepta[4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester (106)

The reaction was carried out as described in the general procedure using chlorinated tricycle 103 (0.45 g, 2.03 mmol) and W-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (0.69 g, 2.23 mmol, 1.1 equiv.) in THF (9 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch / acetone from 90/10 to 50/50 to provide compound 106 (0.50 g, 67%) as a white solid. Rf (CH 2 Ch / acetone 70/30) 0.27. Mp: 180 - 182 °C. 1H NMR (250 MHz, DMSO-de) 811.78 (s, 1H, NH), 8.53 (s, 1H, CH), 5.86 (s, 1H, CH), 4.11 - 3.98 (m, 2H, CH2), 3.65 - 3.51 (m, 2H, CH2), 2.89 - 2.79 (m, 2H, CH2), 2.79 - 2.69 (m, 2H, CH2), 2.63 - 2.53 (m, 2H, CH2), 1.89 - 1.75 (m, 2H, CH2), 1.76 - 1.55 (m, 4H, 2 x CH2), 1.44 (s, 9H, 3 x CH3). HRMS (EI-MS) m/z calcd. for C21H29N4O2 [M+H]+: 369.2285, found: 369.2286.

4-(1,2,3,6-tetrahydropyridin-4-yl)-5,6,7,8-tetrahydrocyclopenta[4,5]pyrrolo[2,3-d]pyrimidine (107)

The reaction was carried out as described in General Procedure F1 using the N-Boc protected compound 104 (1.0 g, 2.94 mmol) in CH 2 Cl 2 (80 mL). The reaction was complete after 1 h. Work-up gave compound 107 (0.65 g, 92%) as a beige solid. Mp: > 260 °C. 1H Rm N (250 MHz, DMSO-d6) 811.91 (brs, 1H, NH), 8.53 (s, 1H, CH), 6.53 (s, 1H, CH), 3.50 - 3.38 (m, 2H, CH2), 2.98 - 2.75 (m, 6H, 3 x CH2), 2.59 - 2.45 (m, 2H, CH2), 2.45 - 2.30 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for C14H17N4 [M+H]+: 241.1448, found: 241.1446.

4-(1,2,3,6-tetrahydropyridin-4-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-6]indole (108)

The reaction was carried out as described in General Procedure F1 using the N-Boc protected compound 105 (1.0 g, 2.82 mmol) in CH 2 Cl 2 (80 mL). The reaction was complete after 1 h. Work-up gave compound 108 (0.68 g, 95%) as a light yellow solid. Mp: 187 - 189 °C. 1H NMR (250 MHz, MeOD-d4) 8 8.51 (s, 1H, CH), 6.03 (tt, J = 3.3, 1.7 Hz, 1H, CH), 3.54 (dt, J = 2.9 Hz, J = 2.9 Hz, 2H, CH2), 3.10 (t, J = 5.7 Hz, 2H, CH2), 2.82 - 2.74 (m, 2H, CH2), 2.71 - 2.63 (m, 2H, CH2), 2.65 - 2.51 (m, 2H, CH2), 2.00 - 1.77 (m, 4H, 2 x CH2). HRMS (EI-MS) m/z calcd. for C15H19N4 [M+H]+: 255.1604, found: 255.1603.

4-(1,2,3,6-tetrahydropyridin-4-yl)-5,6,7,8,9,10-hexahydrocyclohepta[4,5]pyrrolo[2,3-d]pyrimidine ditrifluoroacetate (109)

The reaction was carried out as described in general procedure F2 using the N-Boc protected compound 106 (1.0 g, 2.71 mmol) in CH 2 Cl 2 (80 mL). The reaction was complete after 1 h. Work-up gave compound 109 (1.17 g, 87%) as a yellow solid. Mp: degradation 176 °C. 1H NMR (250 MHz, DMSO-d6) 8 12.32 (brs, 1H, NH), 9.21 (s, 2H, NH H+), 8.70 (s, 1H, CH), 6.08 - 5.95 (m, 1H, CH), 3.92 - 3.79 (m, 2H, CH2), 3.47 - 3.30 (m, 2H, CH2), 2.94 - 2.85 (m, 2H, CH2), 2.82 - 2.71 (m, 4H, 2 x CH2), 1.89 - 1.77 (m, 2H, CH2), 1.76 - 1.58 (m, 4H, 2 x CH2). 19F NMR (235 MHz, DMSO-d6) 8 -74.2 (s). HRMS (EI-MS) m/z calcd. for C16H21N4 [M+H]+: 269.1761, found: 269.1760.

Example 57: N-(3-fluorophenyl)-4-(5,6,7,8-tetrahydrocyclopenta[4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridin-1 (2H)-carboxamide (110)

The reaction was carried out as described in the general procedure by using amine 107 (60 mg, 0.25 mmol) in anhydrous CH 2 Cl 2 (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch / acetone from 80/20 to 30/70 to provide compound 110 (57 mg, 60%) as a light yellow solid. Rf (CH 2 Ch / acetone 70/30) 0.26. Mp: degradation 217 °C. 1H NMR (400 MHz, DMSO-de) 811.96 (brs, 1H, NH), 8.77 (brs, 1H, NH), 8.57 (s, 1H, CH), 7.52 - 7.43 (m, 1H, CH), 7.33 - 7.20 (m, 2H, CH), 6.79 - 6.71 (m, 1H, CH), 6.61 - 6.53 (m, 1H, CH), 4.29 - 4.20 (m, 2H, CH2), 3.71 (t, J = 5.6 Hz, 2H, CH2), 2.92 - 2.82 (m, 4H, 2 x CH2), 2.78 - 2.71 (m, 2H, CH2), 2.46 - 2.37 (m, 2H, CH2). 19F NMR (376 MHz, DMSO-d6) 8 -112.9 (s). HRMS (EI-MS) m/z calcd. for C21H21FN5O [M+H]+: 378.1725, found: 378.1724.

Example 58: N-(3-chlorophenyl)-4-(5,6,7,8-tetrahydrocyclopenta[4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (111)

The reaction was carried out as described in the general procedure by taking amine 107 (60 mg, 0.25 mmol) in anhydrous CH 2 Cl 2 (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch / acetone from 80/20 to 30/70 to provide compound 111 (82 mg, 83%) as a white solid. Rf (CH 2 Ch / acetone 70/30) 0.26. Mp: degradation 208 °C. 1H NMR (400 MHz, DMSO-de) 8 11.96 (brs, 1H, NH), 8.75 (brs, 1H, NH), 8.57 (s, 1H, CH), 7.69 (s, 1H, CH), 7.45 (d, J = 8.3 Hz, 1H, CH), 7.26 (t, J = 8.1 Hz, 1H, CH), 6.98 (d, J = 8.0 Hz, 1H, CH), 6.60 - 6.53 (m, 1H, CH), 4.30 - 4.21 (m, 2H, CH2), 3.71 (t, J = 5.7 Hz, 2H, CH2), 2.91 - 2.81 (m, 4H, 2 x CH2), 2.77 - 2.69 (m, 2H, CH2), 2.46 - 2.37 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for C21H21ClNeO [M+H]+: 394.1429, found: 394.1430.

Example 59: N-(3-bromophenyl)-4-(5,6,7,8-tetrahydrocyclopenta[4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (112)

The reaction was carried out as described in the general procedure by taking amine 107 (60 mg, 0.25 mmol) in anhydrous CH 2 Cl 2 (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch / acetone from 80/20 to 30/70 to provide compound 112 (46 mg, 42%) as a beige solid. Rf (CH 2 Ch / acetone 70/30) 0.25. Mp: degradation 216 °C. 1H NMR (400 MHz, DMSO-de) 8 11.96 (brs, 1H, NH), 8.73 (brs, 1H, NH), 8.57 (s, 1H, CH), 7.83 (s, 1H, CH), 7.50 (d, J = 8.3 Hz, 1H, CH), 7.20 (t, J = 8.0 Hz, 1H, CH), 7.11 (d, J = 8.0 Hz, 1H, CH), 6.57 (s, 1H, CH), 4.26 - 4.21 (m, 2H, CH2), 3.70 (t,J = 5.5 Hz, 2H,CH2), 2.93 - 2.81 (m, 4H, 2 x CH2), 2.78 - 2.69 (m, 2H, CH2), 2.45 - 2.37 (m, 2H,

CH2). HRMS (EI-MS) m/z calcd. for C2iH 2iBrNsO [M+H]+: 438.0924, found: 438.0925.

Example 60: W-(3-fluorophen¡l)-4-(6,7,8,9-tetrahydro-5H-pyramida[4,5-6]ndole-4-¡ l)-3,6-di¡hydro¡r¡d¡n-1(2H)-carboxamide

(113)

The reaction was carried out as described in the general procedure using amine 108 (60 mg, 0.24 mmol) in anhydrous CH2Cl2 (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Cl2/acetone from 80/20 to 20/80 to provide compound 113 (86 mg, 91%) as a light yellow solid. Rf(CH2Cl2/acetone 20/80) 0.27. Mp: degradation

246°C. 1H NMR (400 MHz, DMSO-de) 8 11.75 (brs, 1H, NH), 8.77 (brs, 1H, NH), 8.56 (s, 1H, CH), 7.49 (dt, J =

12.6 Hz, J = 2.1 Hz, 1H, CH), 7.34 - 7.21 (m, 2H, 2 x CH), 6.80 - 6.70 (m, 1H, CH), 6 .12 - 6.03 (m, 1H, CH), 4.26 - 4.16

(m, 2H, CH2), 3.72 (t, J = 5.6 Hz, 2H, CH2), 2.75 - 2.65 (m, 4H, 2 x CH2), 2.58 (t, J = 5.8 Hz, 2H, CH2), 1.87 - 1.78 (m,

2H, CH2), 1.77 - 1.69 (m, 2H, CH2). 19F NMR (376 MHz, DMSO-d6) 8 -112.9 (s). HRMS (EI-MS) m/z calcd. for C22H23

FN 5 O[M+H]+: 392.1881, found: 392.1880.

Example 61: W-(3-chlorophen¡l)-4-(6,7,8,9-tetrahydro-5H-pyramida[4,5-6]ndole-4-¡ l)-3,6-di¡hydro¡r¡d¡n-1(2H)-carboxamide

(114)

The reaction was carried out as described in the general procedure by using amine 108 (60 mg, 0.24 mmol) in anhydrous CH 2 Cl 2 (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch 2 /acetone from 80/20 to 20/80 to afford compound 114 (84 mg, 86%) as a beige solid. Rf (CH 2 Ch 2 /acetone 20/80) 0.28. Mp: deg 177 °C. 1H NMR (400 MHz, DMSO-de) 8 11.77 (brs, 1H, NH), 8.76 (brs, 1H, NH), 8.57 (s, 1H, CH), 7.70 (s, 1H, CH),

7.45 (d, J = 8.4 Hz, 1H, CH), 7.26 (t, J = 8.1 Hz, 1H, CH), 6.99 (d, J = 8.8 Hz, 1H, CH ), 6.08 (s, 1H, CH), 4.26 - 4.18

(m, 2H, CH2), 3.72 (t, J = 5.6 Hz, 2H, CH2), 2.76 - 2.64 (m, 4H, 2 x CH2), 2.61 - 2.55 (m, 2H, CH2), 1.87 - 1.78 (m, 2H,

CH2), 1.78 - 1.68 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for C22H23ClNeO [M+H]+: 408.1586, found: 408.1584.

Example 62: W-(3-bromophen¡l)-4-(6,7,8,9-tetrahydro-5H-pyramida[4,5-6]ndole-4-¡ l)-3,6-di¡hydro¡r¡d¡n-1(2H)-carboxamide

(115)

The reaction was carried out as described in the general procedure by using amine 108 (60 mg, 0.24 mmol) in anhydrous CH 2 Cl 2 (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch 2 /acetone from 80/20 to 20/80 to give compound 115 (95 mg, 87%) as a beige solid. Rf (CH 2 Ch 2 /acetone 20/80) 0.28. Mp: deg 198 °C. 1H NMR (400 MHz, DMSO-de) 811.75 (brs, 1H, NH), 8.74 (brs, 1H, NH), 8.56 (s, 1H, CH), 7.86 - 7.80 (m, 1H,

CH), 7.50 (d, J = 8.1 Hz, 1H, CH), 7.21 (t, J = 8.0 Hz, 1H, CH), 7.12 (d, J = 8.7 Hz, 1H, CH), 6.07 (s, 1H, CH), 4.26 -4.16 (m, 2H, CH2), 3.71 (t, J = 5.6 Hz, 2H, CH2), 2.73 (t, J = 5.9 Hz, 2H, CH2), 2.69 - 2.66 (m, 2H, CH2), 2.57 (t, J =

5.7 Hz, 2H, CH2), 1.88 - 1.79 (m, 2H, CH2), 1.78 - 1.68 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for C22H23BrNeO [M+H]+: 452.1080, found: 452.1079.

Example 63: W-(3-fluorophen¡l)-4-(5,6,7,8,9,10-hexah¡droc¡chlohepta[4,5]pyrrolo[2,3-d]p¡ r¡m¡d¡n-4-¡l)-3,6-di¡hydro¡r¡d¡n-1(2H)-carboxamide (116)

The reaction was carried out as described in the general procedure by taking amine 109 (60 mg, 0.16 mmol) in anhydrous CH 2 Cl 2 (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Cl 2 /acetone from 100/0 to 30/70 to give compound 116 (54 mg, 84%) as a beige solid. Rf (CH 2 Cl 2 /acetone 60/40) 0.27. Mp: deg 151 °C. 1H NMR (400 MHz, DMSO-de) 8 11.80 (brs, 1H, NH), 8.79 (brs, 1H, NH), 8.55 (s, 1H, H2 CH), 7.49 (dt, J =

12.3 Hz, J = 2.2 Hz, 1H, CH), 7.33 - 7.22 (m, 2H, 2 x CH), 6.81 - 6.69 (m, 1H, CH), 5 .97 - 5.85 (m, 1H, CH), 4.23 - 4.15

(m, 2H, CH2), 3.73 (t, J = 5.6 Hz, 2H, CH2), 2.88 - 2.80 (m, 2H, CH2), 2.80 - 2.73 (m , 2H, CH2), 2.70 - 2.64 (m, 2H,

CH2), 1.85 - 1.77 (m, 2H, CH2), 1.73 - 1.66 (m, 2H, CH2), 1.65 (s, 2H, CH2). 19F NMR (376 MHz, DMSO-d6) 8 -112.9

(s). HRMS (EI-MS) m/z calcd. for C19H19FN5O [M+H]+: 406.2038, found: 406.2035.

Example____ 64: W-(3-chlorophen¡l)-4-(5,6,7,8,9,10-hexah¡droc¡chlohepta[4,5]pyrrolo[2,3-d]p¡ r¡m¡d¡n-4-¡l)-3,6-di¡hydro¡r¡d¡n-1(2H)-carboxamide (117)

The reaction was carried out as described in the general procedure by using amine 109 (60 mg, 0.16 mmol) in anhydrous CH 2 Cl 2 (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Cl 2 /acetone from 100/0 to 30/70 to afford compound 117 (63 mg, 94%) as a beige solid. Rf (CH 2 Cl 2 /acetone 60/40) 0.27. Mp: deg 163 °C. 1H NMR (400 MHz, DMSO-de) 8 11.80 (brs, 1H, NH), 8.77 (brs, 1H, NH), 8.55 (s, 1H, CH), 7.70 (s, 1H, CH),

7.45 (d, J = 8.4 Hz, 1H, CH), 7.27 (t, J = 8.1 Hz, 1H, CH), 6.99 (d, J = 8.2 Hz, 1H, CH ), 5.96 - 5.87 (m, 1H, CH), 4.27 -4.10 (m, 2H, CH2), 3.73 (t, J = 5.6 Hz, 2H, CH2), 2.88 - 2.81 (m, 2H, CH2), 2.80 - 2.72 (m, 2H, CH2), 2.71 - 2.62 (m, 2H,

CH2), 1.84 - 1.77 (m, 2H, CH2), 1.72 - 1.66 (m, 2H, CH2), 1.66 - 1.60 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for C23H25ClNeO [M+H]+: 422.1742, found: 422.1740.

Example 65: W-(3-bromophen¡l)-4-(5,6,7,8,9,10-hexah¡droc¡chlohepta[4,5]p¡rrolo[2,3-d]p¡ r¡m¡d¡n-4-¡l)-3,6-di¡hydro¡r¡d¡n-1(2H)-carboxamide (118)

The reaction was carried out as described in the general procedure using amine 109 (60 mg, 0.16 mmol) in anhydrous CH 2 Cl 2 (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Cl 2 /acetone from 100/0 to 30/70 to give compound 118 (61 mg, 82%) as a beige solid. Rf (CH 2 Ch /acetone 60/40) 0.28. Mp: degradation 178 °C. 1H NMR (400 MHz, DMSO-de) 8 11.80 (brs, 1H, NH), 8.75 (brs, 1H, NH), 8.55 (s, 1H, CH), 7.83 (s, 1H, CH), 7.50 (d, J = 8.2 Hz, 1H, CH), 7.21 (t, J = 7.9 Hz, 1H, CH), 7.12 (d, J = 8.0 Hz, 1H, CH), 5.98 - 5.86 (m, 1H, CH), 4.26 -4.13 (m, 2H, CH2), 3.72 (t, J = 5.5 Hz, 2H, CH2), 2.88 - 2.80 (m, 2H, CH2), 2.80 - 2.73 (m, 2H, CH2), 2.70 - 2.62 (m, 2H, CH2), 1.85 - 1.76 (m, 2H, CH2), 1.73 - 1.66 (m, 2H, CH2), 1.66 - 1.60 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for C23H25BrN5O [M+H]+: 466.1237, found: 466.1234.

Example 66: W-phen¡l-4-(5,6,7,8-tetrah¡droc¡clopenta[4,5]p¡rrolo[2,3-d]p¡r¡m¡d¡n- 4-¡l)-3,6-di¡hydro¡r¡din-1(2H)-carboxamide (119)

The reaction was carried out as described in the general procedure by using amine 107 (60 mg, 0.25 mmol) in anhydrous CH 2 Cl 2 (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Cl 2 /acetone from 100/0 to 40/60 to give compound 119 (47 mg, 75%) as a light yellow solid. Rf (CH 2 Cl 2 /acetone 50/50) 0.24. Mp: degradation 215 °C. 1H NMR (250 MHz, MeOD-d4) 88.54 (s, 1H, CH), 7.47 - 7.35 (m, 2H, 2 x CH), 7.35 - 7.21 (m, 2H, 2 x CH), 7.09 - 6.97 (m, 1H, CH), 6.57 - 6.43 (m, 1H, CH), 4.36 - 4.27 (m, 2H, CH2), 3.81 (t, J = 5.6 Hz, 2H, CH2), 3.03 - 2.86 (m, 4H, 2 x CH2), 2.86 - 2.73 (m, 2H, CH2), 2.61 - 2.40 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for C21H22N5 O[M+H]+: 360.1819, found: 360.1819.

Example 67: W-phen¡l-4-(6,7,8,9-tetrahydro-5H-pyrimid[4,5-6]ndole-4-¡l)-3 ,6-d¡hydro¡r¡d¡n-1(2H)-carboxamide (120)

The reaction was carried out as described in the general procedure using amine 108 (60 mg, 0.25 mmol) in anhydrous CH 2 Cl 2 (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch 2 /acetone from 80/20 to 80/20 to give compound 207 (69 mg, 78%) as a white solid. R f (CH 2 C f c /acetone 20/80) 0.20. Mp: 255 - 257 °C. 1H NMR (400 MHz, DMSO-de) 811.74 (brs, 1H, NH), 8.56 (s, 2H, NH CH), 7.50 (d, J = 8.0 Hz, 2H, 2 x CH), 7.24 (t, J = 7.7 Hz, 2H, 2 x CH), 6.94 (t, J = 7.3 Hz, 1H, CH), 6.07 (s, 1H, CH), 4.27 - 4.12 (m, 2H, CH2), 3.71 (t, J = 5.6 Hz, 2H, CH2), 2.78 - 2.63 (m, 4H, 2 x CH2), 2.63 - 2.54 (m, 2H, CH2), 1.87 - 1.77 (m, 2H, CH2), 1.77 - 1.69 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for C22H24N5 O[M+H]+: 374.1975, found: 374.1972.

Example 68: W-(3-methoxy¡phen¡l)-4-(5,6,7,8-tetrah¡droc¡clopenta[4,5]p¡rrolo[2,3-d]p¡r¡ m¡d¡n-4-¡l)-3,6-di¡hydro¡r¡d¡n-1(2H)-carboxamide (121)

The reaction was carried out as described in the general procedure using amine 107 (60 mg, 0.25 mmol) in anhydrous CH 2 Cl 2 (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch 2 /acetone from 100/0 to 40/60 to give compound 121 (55 mg, 89%) as a white solid. R f (CH 2 Ch 2 /acetone 50/50) 0.21. Mp: degradation 206 °C. 1H NMR (250 MHz, MeOD-d4) 88.54 (s, 1H, CH), 7.16 (t, J = 8.1 Hz, 1H, CH), 7.09 (t, J = 2.2 Hz, 1H, CH), 6.97 (ddd, J = 8.1 Hz, J = 2.0 Hz, J = 1.0 Hz, 1H, CH), 6.60 (ddd, J = 8.2 Hz, J = 2.5 Hz, J = 1.0 Hz, 1H, CH), 6.48 (m, 1H, CH), 4.34 - 4.25 (m, 2H, CH2), 3.80 (t, J = 5.6 Hz, 2H, CH2), 3.78 (s, 3H, OCH3), 3.05 - 2.85 (m, 4H, 2 x CH2), 2.85 - 2.73 (m, 2H, CH2), 2.62 - 2.42 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for C22H24NeO2[M+H]+: 390.1925, found: 390.1923.

Example 69: 3-(4-(5,6,7,8-tetrah¡droc¡clopenta[4,5]p¡rrolo[2,3-d]p¡r¡m¡d¡n-4 carbamate -¡l)-1,2,3,6-tetrah¡drop¡r¡dina-1-carboxam¡do)phen¡ld¡methyl (122)

The reaction was carried out as described in the general procedure using 3-aminophenyl dimethylcarbamate (45 mg, 0.25 mmol) and amino107 (72 mg, 0.30 mmol, 1.2 equiv.) in THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Ch/acetone from 80/20 to 10/90 to provide compound122 (99 mg, 89%) as a light yellow solid. Rf (CH2Cl2/acetone 20/80) 0.24. Mp: 227 - 229 °C. 1H NMR (250 MHz, DMSO-de) 811.96 (s, 1H, NH), 8.68 (brs, 1H, NH), 8.58 (s, 1H, H2), 7.38 (d, J = 2.2 Hz, 1H, CH), 7.32 (d, J = 8.1 Hz, 1H, CH), 7.22 (t, J = 8.0 Hz, 1H, CH), 6.69 (d, J = 7.9 Hz, 1H, CH), 6.62 - 6.53 (m, 1H, CH), 4.36 - 4.18 (m, 2H, CH2), 3.70 (t, J = 5.3 Hz, 2H, CH2), 3.03 (s, 3H, NCH3), 2.97 - 2.81 (m, 7H, 2 x CH2 NCH3), 2.80 - 2.69 (m, 2H, CH2), 2.46 - 2.35 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for C24H27N6O3 [M+H]+: 447.2139, found: 447.2141.

Example 70: W-([1,1'-biphen¡l]-3-¡l)-4-(5,6,7,8-tetrahydroc¡clopenta[4,5]p¡rrolo[ 2,3-d]p¡r¡m¡d¡n-4-¡l)-3,6-d¡hídrop¡r¡d¡n-1(2H)-carboxamide (123)

The reaction was carried out as described in the general procedure using 3-aminobiphenyl (42 mg, 0.25 mmol) and amine 107 (72 mg, 0.30 mmol, 1.2 equiv.) in THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch /acetone from 80/20 to 10/90 to provide compound 123 (63 mg, 58%) as a white solid.

Rf(CH2Cl2/acetone 50/50) 0.26. Mp: 245 - 247 °C. 1H NMR (250 MHz, DMSO-de) 811.96 (brs, 1H, NH), 8.66 (brs, 1H, NH), 8.58 (s, 1H, CH), 7.87 - 7.78 (m, 1H, CH), 7.66 - 7.58 (m, 2H, 2 x CH), 7.57 - 7.41 (m, 3H, 3 x CH), 7.40 - 7.28 (m, 2H, 2 x CH), 7.28 - 7.17 (m, 1H, CH), 6.66 - 6.52 ( m, 1H, CH), 4.32 - 4.23 (m, 2H, CH2), 3.73 (t, J = 5.5 Hz, 2H, CH2), 2.94 - 2.81 (m, 4H, 2 x CH2), 2.79 - 2.70 (m, 2H, CH2), 2.48 - 2.35 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for C27H26N5 O[M+H]+: 436.2132, found: 436.2131.

Example____ 71: W-(3-(pyridin-4yl)phenyl)-4-(5,6,7,8-tetrahydrocyclopenta[4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3, 6-dihydropyridine-1(2H)-carboxamide (124)

The reaction was carried out as described in the general procedure using 3-(pyridin-4-yl)aniline (43 mg, 0.25 mmol) and amine 107 (72 mg, 0.30 mmol, 1.2 equiv.) in THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Cl 2 /acetone from 60/40 to 0/100 to provide compound 124 (84 mg, 77%) as an off-white solid. Rf (acetone) 0.16. Mp: > 260 °C. 1H NMR (400 MHz, DMSO-de) 8 11.97 (brs, 1H, NH), 8.74 (brs, 1H, NH), 8.64 (d, J = 5.7 Hz, 2H, 2 x CH), 8.58 (s, 1H, CH), 7.98 - 7.93 (m, 1H, CH), 7.66 - 7.61 (m, 3H, 3 x CH), 7.44 - 7.34 (m, 2H, 2 x CH), 6.64 - 6.56 (m, 1H, CH), 4.32 - 4.24 (m, 2H, CH2), 3.74 (t, J = 5.6 Hz, 2H, CH2), 2.92 - 2.82 (m, 4H, 2x CH2), 2.80 - 2.72 (m, 2H, CH2), 2.46 - 2.37 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for C26H25N6 O[M+H]+: 437.2084, found: 437.2080.

Example 72: W-(3-phenoxyphenyl)-4-(5,6,7,8-tetrahydrocyclopenta[4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridin-1 (2H)-carboxamide (125)

The reaction was carried out as described in the general procedure by using amine 107 (60 mg, 0.25 mmol) in anhydrous CH 2 Cl 2 (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch / acetone from 80/20 to 30/70 to provide compound 125 (67 mg, 59%) as a yellow solid. R f (CH 2 C f c / acetone 50/50) 0.26. Mp: degradation 154 °C. 1H NMR (400 MHz, DMSO-de) 811.96 (brs, 1H, NH), 8.64 (brs, 1H, NH), 8.57 (s, 1H, CH), 7.39 (t, J = 7.8 Hz, 2H, 2 x CH), 7.33 - 7.20 (m, 3H, 3 x CH), 7.13 (t, J= 7.4 Hz, 1H, CH), 7.01 (d, J = 8.0 Hz, 2H, 2 x CH), 6.61 (d, J = 8.0 Hz, 1H, CH), 6.58 - 6.53 (m, 1H, CH), 4.25 - 4.16 (m, 2H, CH2), 3.68 (t, J = 5.6Hz, 2H, CH2), 2.91 - 2.81 (m, 4H, 2 x CH2), 2.76 - 2.67 (m, 2H, CH2), 2.45 - 2.37 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for C27H26N5O2 [M+H]+: 452.2081, found: 452.2079.

Example 73: N-(3-phenoxyphenyl)-4-(6,7,8,9-tetrahydro-5H-pyrimido[4,5-b]indol-4-yl)-3,6-dihydropyridin-1(2H )-carboxamide (126)

The reaction was carried out as described in general procedure G using amine 108 (60 mg, 0.24 mmol) in anhydrous CH2Cl2 (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Ch/acetone from 80/20 to 20/80 to afford compound126 (87 mg, 81%) as an off-white solid. Rf (CH2Ch/acetone 20/80) 0.31. Mp: degradation 171 °C. 1H NMR (400 MHz, DMSO-de) 811.74 (brs, 1H, NH), 8.65 (brs, 1H, NH), 8.56 (s, 1H, CH), 7.39 (t, J = 7.8 Hz, 2H, 2 x CH), 7.34 - 7.20 (m, 3H, 3 x CH), 7.13 (t, J = 7.4 Hz, 1H, CH), 7.01 (d, J = 8.0 Hz, 2H, 2 x CH), 6.61 (d, J = 8.0 Hz, 1H, CH), 6.08 - 6.01 (m, 1H, CH), 4.23 - 4.11 (m, 2H, CH2), 3.69 (t, J = 5.6Hz, 2H, CH2), 2.75 - 2.69 (m, 2H, CH2), 2.69 - 2.63 (m, 2H, CH2), 2.60 - 2.54 (m, 2H, CH2), 1.86 - 1.78 (m, 2H, CH2), 1.78 - 1.68 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for C26H26N5O2 [M+H]+: 466.2238, found: 466.2236.

Example 74: N-(3-cyanophenyl)-4-(7,9,11-triazatricyclo[6.4.0.02,6] dodeca-1(8),2(6),9,11-tetraen-12-yl)-3,6-dihydropyridine-1(2H)-carboxamide (127)

The reaction was carried out as described in the general procedure Gusando 107. HCl (50 mg, 0.16 mmol) in anhydrous CH 2 Cl 2 (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch / acetone from 100/0 to 40/60 to provide compound 127 (42 mg, 69%) as a white solid. R f (CH 2 Cfc / acetone 50/50) 0.4. Mp: degradation > 266 °C. 1H NMR (250 MHz, DMSO-de) 811.97 (s, 1H), 8.92 (s, 1H), 8.58 (s, 1H), 7.98 (s, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.57 - 7.30 (m, 2H), 6.58 (s, 1H), 4.34 - 4.13 (m, 2H), 3.72 (t, J = 5.8 Hz, 2H), 2.94 - 2.81 (m, 4H), 2.76 (brs, 2H), 2.47 - 2.33 (m, 2H). HRMS (EI-MS) m/z calcd. for C22H21N6 O[M+H]+: 385.1771, found: 385.1768.

Item 75: 4-(7,9,11-triazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),9,11-tetraen-12-yl)-N[3(trifluoromethyl)phenyl ]-3,6-dihydropyridine-1(2H)-carboxamide (128)

The reaction was carried out as described in the general procedure using the amine salt 107.HCl (50 mg, 0.15 mmol) in anhydrous CH 2 Cl 2 (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch / acetone from 100/0 to 50/50 to afford compound 128 (55 mg, 80%) as a white solid. Rf (CH 2 Ch / acetone 50/50) 0.22. Mp: degradation 220 °C. 1H NMR (250 MHz, DMSO-de) 811.90 (s, 1H, NH), 8.86 (s, 1H, NH), 8.57 (s, 1H, CH), 7.96 (s, 1H, CH), 7.80 (d, J = 8.4 Hz, 1H, CH), 7.48 (t, J = 8.0 Hz, 1H, CH), 7.27 (d, J = 8.2 Hz, 1H, CH), 6.73 - 6.46 (m, 1H, CH), 4.31 - 4.23 (m, 2H, CH2), 3.73 (t, J = 5.6 Hz, 2H, CH2), 2.95 - 2.81 (m, 4H, CH2), 2.75 (brs, 2H, CH2), 2.47 - 2.32 (m, 2H, CH2). 19F NMR (235 MHz, DMSO-d6) 8 -61.26 (CF3). HRMS (EI-MS) m/z calcd. for C22H21F3N5O [M+H]+: 428.1693, found: 428.1690.

Example 76: W-(3-ethylphen¡l)-4-(7,9,11-tr¡azatr¡cyclo[6.4.0.02,6]dodeca-1(8),2(6), 9,11-tetraen-12-¡l)-3,6-di¡hydro¡r¡dina-1(2H)-carboxamide (129)

The reaction was carried out as described in the general procedure using amine salt 107.HCl (58 mg, 0.19 mmol) in THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Ch/acetone from 100/0 to 60/40 to give compound 129 (45 mg, 75%) as a light yellow solid. Rf (CH2Cl2/acetone 70/30) 0.24. Mp: degradation 192 °C. 1H NMR (250 MHz, MeOD-d4) 88.54 (s, 1H, CH), 7.35 - 7.10 (m, 3H, CH), 6.97 - 6.81 (m, 1H, CH), 6.48 (s, 1H, CH), 4.36 - 4.20 (m, 2H, CH2), 3.79 (t, J = 5.6 Hz, 2H, CH2), 2.99 - 2.84 (m, 4H, CH2), 2.80 (s, 2H, CH2), 2.69 -2.41 (m, 4H, CH2), 1.23 (t, J = 7.6 Hz, 3H, CH3). HRMS (EI-MS) m/z calcd. for C23H26N5 O[M+H]+: 388.2132, found: 388.2130.

Example _______ 77: N-(3-morphol¡nophen¡l)-4-(7,9,11-tr¡azatr¡cyclic[6A0.02,6]dodeca-1(8),2(6) ,9,11-tetraen-12-¡l)-3,6-di¡hydro¡r¡dina-1(2H)-carboxamide (130)

The reaction was carried out as described in the general procedure using amine salt 107.HCl (51 mg, 0.16 mmol) in THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Cl2/acetone from 100/0 to 40/60 to provide 130 (40 mg, 67%) as a light yellow solid. Rf (CH2Ch/acetone 30/70) 0.32. Mp: degradation 250 °C. 1H NMR (250 MHz, DMSO-de) 811.96 (s, 1H, NH), 8.57 (s, 1H, CH), 8.42 (s, 1H, NH), 7.30 - 6.90 (m, 3H, CH), 6.57 (brs, 2H, CH CH), 4.24 (s, 2H, CH2), 3.86 - 3.58 (m, 6H, CH2), 3.05 (brs, 4H, CH2), 2.87 (brs, 4H, CH2), 2.73 (s, 2H, CH2), 2.45 - 2.29 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for C25H29N6O2[M+H]+: 445.2347, found: 445.2347.

Example 78: N-[3-(dimet¡lcarbamo¡lano(phen¡l)]-4-(7,9,11-tr¡azatr¡cyclic[6.4.0.02,6] dodeca- 1(8),2(6),9,11-tetraen-12-¡l)-3,6-d¡hídrop¡r¡d¡na-1 (2H)-[131)

The reaction was carried out as described in the general procedure using amine salt 107.HCl (51 mg, 0.16 mmol) in THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Cl2/acetone/MeOH from 100/0/0 to 0/95/5 to provide compound 131 (37 mg, 62%) as a white solid. Rf (acetone) 0.42. Mp: degradation 208 °C. 1H NMR (250 MHz, DMSO-de) 811.99 (s, 1H, NH), 8.58 (s, 1H, CH), 8.52 (s, 1H, NH), 8.20 (s, 1H, NH), 7.66 (s, 1H, CH), 7.06 (s, 3H, CH), 6.57 (s, 1H, CH), 4.24 (s, 2H, CH2), 3.69 (t, J = 5.4 Hz, 2H, CH2), 2.98 - 2.80 (m, 10H, 2x CH3 2x CH2), 2.73 (s, 2H, CH2), 2.46 - 2.30 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for C24H28N7O2 [M+H]+: 446.2299, found: 446.2300.

Example 79: W-[3-[(dimethyllamino)methyl]phenyl]-4-(7,9.11-trace-tracycle[6.4.0.02,6] dodeca-1(8),2(6),9,11-tetraen-12-¡l)-3,6-di¡hydro¡r¡d¡n-1 (2H)-carboxamide (132)

The reaction was carried out as described in general procedure H using amine salt 107.HCl (54 mg, 0.17 mmol) in THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Ch/acetone (0.1% aq. NH3) from 100/0 to 86/14 to provide compound 132 (25 mg, 42%) as a light yellow solid. Rf (CH2Cb/ MeOH/ aq. NH3 91/9/0.1) 0.21. Mp: degradation 180 °C. 1H NMR (250 MHz, DMSO-de) 8 11.97 (s, 1H, NH), 8.70 - 8.43 (m, 2H, NH CHar), 7.50 (s, 1H, CH), 7.44 (d, J = 8.3 Hz, 1H, CH), 7.21 (t, J = 7.8 Hz, 1H, CH), 6.91 (d, J = 7.5 Hz, 1H, CH), 6.57 (s, 1H, CH), 4.25 (s, 2H, CH2), 3.70 (t, J = 4.4 Hz, 2H, CH2), 3.50 (s, 2H, CH2), 3.08 - 2.80 (m, 4H, CH2), 2.73 (s, 2H, CH2), 2.45 - 2.32 (m, 2H, CH2), 2.25 (s, 6H, CH3). HRMS (EI-MS) m/z calcd. for C24H29N6 O[M+H]+: 417.2397, found: 417.2397.

Example____ 80. W-[3-(met¡lcarbamo¡l)phen¡l]-4-(7,9,11-tr¡azatr¡cycle[6.4.0.02,6]dodeca-1(8), 2(6),9,11-tetraen-12-¡l)-3,6-d¡hdrop¡r¡d¡na-1 (2H)-[133)

The reaction was carried out as described in the general procedure using amine salt 107.HCl (53 mg, 0.17 mmol) in THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Ch/acetone from 100/0 to 10/90 to provide compound 133 (55 mg, 94%) as a white solid. Rf (CH2Ch/acetone 10/90) 0.27. Mp: degradation 228 °C. 1H NMR (250 MHz, DMSO-de) 811.96 (s, 1H, NH), 8.74 (s, 1H, NH), 8.58 (s, 1H, CH), 8.39 - 8.28 (m, 1H, CH), 7.95 (s, 1H, CH), 7.68 (d, J = 8.1 Hz, 1H, CH), 7.47 - 7.22 (m, 2H, CH), 6.58 (s, 1H, CH), 4.27 (s, 2H, CH2), 3.72 (t, J = 5.5 Hz, 2H, CH2), 2.94 - 2.81 (m, 4H, 2 x CH2), 2.81 - 2.67 (m, 5H, CH2, CH3), 2.46 - 2.37 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for C23H25N6O2[M+H]+: 417.2033, found: 417.2034.

Example 81: W-[3-(dimet¡lcarbamo¡l)feml]-4-(7,9,11-triazatincide[6.4.0.02,6]dodeca-1(8),2(6),9 ,11-tetraen-12-¡l)-3,6-dihydropyridine-1 (2H)-[134)

The reaction was carried out as described in the general procedure using amine salt 107.HCl (52 mg, 0.17 mmol) in THF (4 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch / acetone from 100/0 to 05/95 to provide compound 134 (50 mg, 83%) as a white solid. Rf (acetone) 0.21. Mp: degradation 245 °C 1H NMR (400 MHz, DMSO-de) 8 11.96 (s, 1H, NH), 8.70 (s, 1H, NH), 8.57 (s, 1H, CH), 7.59 - 7.53 (m, 2H, CH), 7.30 (t, J = 7.8 Hz, 1H, CH), 6.95 (d, J = 7.6, Hz, 1H, CH), 6.62 - 6.52 (m, 1H, CH), 4.28 - 4.24 (m, 2H, CH2), 3.71 (t, J = 5.5 Hz, 2H, CH2), 3.03 - 2.81 (m, 10H, CH3 CH2), 2.74 (m, 2H, CH2), 2.48 - 2.34 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for C24H26N6O2[M+H]+: 431.2190, found: 431.2189.

Example 82: W-[3-(methoxy¡methoxy¡methyl)phen¡l]-4-(7,9,11-tr¡azatr¡cyclo[6.4.0.02,6]dodeca-1(8 ),2(6),9,11-tetraen-12-¡l)-3,6-dihydropyridine-1 (2H)-[135)

The reaction was carried out as described in the general procedure using amine salt 107.HCl (113 mg, 0.36 mmol) in THF (8 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch / acetone from 100/0 to 30/70 to provide compound 135 (120 mg, 92%) as a white solid. Rf (CH 2 Ch / acetone 30/70) 0.35. Mp: degradation 196 °C. 1H NMR (250 MHz, DMSO-de) 8 11.95 (s, 1H, NH), 8.67 - 8.49 (m, 2H, NH CH), 7.58 - 7.35 (m, 2H, CH), 7.21 (t, J = 7.7 Hz, 1H, CH), 6.90 (d, J = 7.4 Hz, 1H, CH), 6.65 - 6.43 (m, 1H, CH), 4.64 (s, 2H, CH2), 4.47 (s, 2H, CH2), 4.2 (s, 2H, CH2), 3.70 (t, J = 5.3 Hz, 2H, CH2), 3.30 (s, 3H, CH3), 2.99 - 2.80 (m, 4H, CH2), 2.73 (s, 2H, CH2), 2.47 -2.33 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for C24H2sN5O3[M+H]+: 434.2187, found: 434.2186.

Example _________83: N-[3-(4-methoxy¡phen¡l)phen¡l]-4-(7,9,11-tr¡aza-6.4.0.02,6]dodeca-1(8),2( 6),9,11-tetraen-12-¡l)-3,6-dihydropyridine-1 (2H)-carboxamide (136)

The reaction was carried out as described in General ProcedureHusando107.HCl(48 mg, 0.15 mmol) in THF (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Ch/acetone from 100/0 to 10/90 to afford compound136(45 mg, 75%) as a pale yellow solid. Rf (CH2Ch/acetone 20/80) 0.56. Mp: degradation 240 °C. 1H NMR (400 MHz, DMSO-de) 811.96 (s, 1H, NH), 8.63 (s, 1H, NH), 8.58 (s, 1H, CH), 7.77 (s, 1H, CH), 7.55 (d, J = 8.3 Hz, 2H, CH), 7.48 (d, J = 8.1 Hz, 1H, CH), 7.30 (t, J = 7.9 Hz, 1H, CH), 7.19 (d, J = 7.7 Hz, 1H, CH), 7.02 (d, J = 8.3 Hz, 2H, CH), 6.59 (s, 1H, CH), 4.27 (s, 2H, CH2), 3.79 (s, 3H, CH3), 3.73 (t, J = 4.8 Hz, 2H, CH2), 2.88 (s, 4H, CH2), 2.75 (s, 2H, CH2), 2.47 - 2.36 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for C28H28N5O2 [M+H]+: 466.2238, found: 466.2240.

Example 84: N-[3-(3-methoxy¡phen¡l)phen¡l]-4-(7,9,11-tr¡azatr¡cyclo[6.4.0.02,6]dodeca-1(8 ),2(6),9,11-tetraen-12-¡l)-3,6-dihydropyridine-1 (2H)-[137)

The reaction was carried out as described in the general procedure using amine salt 107.HCl (48 mg, 0.15 mmol) in THF (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Ch/acetone from 100/0 to 40/60 to afford compound 137 (34 mg, 57%) as a white solid. Rf (CH2Ch/acetone 40/60) 0.53. Mp: degradation 208 °C. 1H NMR (400 MHz, DMSO-de) 811.96 (s, 1H, NH), 8.65 (s, 1H, NH), 8.58 (s, 1H, CH), 7.80 (s, 1H, CH), 7.55 (d, J = 8.0 Hz, 1H, CH), 7.38 (t, J = 8.0 Hz, 1H, CH), 7.33 (t, J = 7.9 Hz, 1H, CH), 7.24 (d, J = 8.3 Hz, 1H, CH), 7.18 (d, J = 7.7 Hz, 1H, CH), 7.13 (s, 1H, CH), 6.94 (dd, J = 8.2, 2.5 Hz, 1H, CH), 6.59 (s, 1H, CH), 4.31 - 4.23 (m, 2H, CH2), 3.82 (s, 3H, CH3), 3.73 (t, J = 5.6 Hz, 2H, CH2), 2.97 - 2.84 (m, 4H, CH2), 2.76 (s, 2H, CH2), 2.47 - 2.37 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for C28H28N5O2 [M+H]+: 466.2238, found: 466.2232.

Family 7.

Tricyclic derivatives with a heteroalkyl ring in the 2 and 3 positions of the pyrrolopyridine and an unsubstituted hydropyridine

x = o, s, nch3

6-(2-(tetrahydro-4H-thiopyran-4-Miden)hydrazinyl)pyrimidin-4-ol (138)

The reaction was carried out as described in the general procedure using 4-hydroxy-6-hydrazinylpyrimidine (1.0 g, 7.93 mmol) and tetrahydro-4H-thiopyran-4-one (1.38 mL, 11.89 mmol, 1.5 equiv.) in EtOH (16 mL). The precipitate was filtered and washed with Et2O (2 x 20 mL) to give compound138 (1.51 g, 85%) as a white solid. Rf (CH2Cl2/acetone 50/50) 0.14. Mp: > 260 °C. 1H NMR (250 MHz, DMSO-de) 811.67 (brs, 1H, OH), 9.77 (s, 1H, NH), 7.90 (d, J= 0.8 Hz, 1H, CH), 5.56 (d, J= 0.8 Hz, 1H, CH), 2.81 - 2.67 (m, 6H, 3 x CH2), 2.61 - 2.53 (m, 2H, CH2). HRMS (EI-MS): m/z calcd. for C9H13N4OS [M+H]+: 225.0805, found: 225.0804.

6-(2-(tetrahydro-4H-pyran-4-ylidene)hydrazinyl)pyrimidin-4-ol (139)

The reaction was carried out as described in the general procedure using 4-hydroxy-6-hydrazinylpyrimidine (1.0 g, 7.93 mmol) and tetrahydro-4H-pyran-4-one (1.11 mL, 11.89 mmol, 1.5 equiv.) in EtOH (16 mL). The precipitate was filtered and washed with Et2O (2 x 20 mL) to give compound139 (1.28 g, 77%) as a beige solid. Rf (CH2Cl2/acetone 50/50) 0.06. Mp: > 260 °C. 1H NMR (250 MHz, DMSO-de) 811.65 (brs, 1H, OH), 9.74 (s, 1H, NH), 7.89 (d, J = 0.8 Hz, 1H, CH), 5.56 (d, J = 0.8 Hz, 1H, CH), 3.73 (t, J = 5.7 Hz, 2H, CH2), 3.65 (t, J = 5.8 Hz, 2H, CH2), 2.55 (t, J = 5.8 Hz, 2H, CH2), 2.36 (t, J = 5.6 Hz, 2H, CH2 HRMS (EI-MS) m/z calcd. for C9H13N4O2 [M+H]+: 209.1033, found: 209,1032.

Benzyl 4-(2-(6-hydroxypyrimidin-4-yl)hydrazono)piperidine-1-carboxylate (140)

The reaction was carried out as described in the general procedure using 4-hydroxy-6-hydrazinylpyrimidine (1.0 g, 7.93 mmol) and 1-CBZ-4-piperidone (2.77 g, 11.89 mmol, 1.5 equiv.) in EtOH (16 mL). The precipitate was filtered and washed with Et2O (2 x 20 mL) to give compound140 (2.41 g, 89%) as a white solid. Rf (CH2Cl2/acetone 50/50) 0.11. Mp: 242 - 244 °C. 1H NMR (250 MHz, DMSO-de) 811.67 (brs, 1H, OH), 9.72 (s, 1H, NH), 7.90 (d, J = 0.9 Hz, 1H, CH), 7.50 - 7.19 (m, 5H, 5 x CH), 5.56 (d, J = 0.8 Hz, 1H, CH), 5.10 (s, 2H, OCH2), 3.60 - 3.47 (m, 4H, 2 x CH2), 2.55 (t, J = 6.3 Hz, 2H, CH2), 2.41 (t, J= 6.3 Hz, 2H, CH2). HRMS (EI-MS) m/z calcd. for C17H20N5O3 [M+H]+: 342.1561, found: 342.1560.

5.7.8.9- tetrahydrothiopyrano[3',4':4,5]pyrrolo[2,3-d]pyrimidin-4-ol (141)

The reaction was carried out as described in the general procedure using hydrazone 138 (0.5 g, 2.23 mmol) in tetralin (10 mL). The precipitate was filtered and washed several times with PE (3 x 10 mL) and Et2O (10 mL) to afford compound141 (0.40 g, 86%) as a brown solid. Rf (CH2Ch/MeOH/NH4OH 90/9/1) 0.39. Mp: > 260 °C. 1H NMR (250 MHz, DMSO-de) 811.70 (brs, 1H, OH), 11.60 (s, 1H, NH), 7.73 (s, 1H, CH), 3.85 - 3.76 (m, 2H, CH2), 2.96 - 2.75 (m, 4H, 2 x CH2). HRMS (EI-MS): m/z calcd. for C9H10N3OS [M+H]+: 208.0539, found: 208.0538.

5.7.8.9- tetrahydrothiopyrano[3',4':4,5]pyrrolo[2,3-d]pyrimidin-4-ol (142)

The reaction was carried out as described in general procedure B using hydrazone139(0.5 g, 2.40 mmol) in tetralin (10 mL). The precipitate was filtered and washed several times with PE (3 x 10 mL) and Et2O (10 mL) to afford compound142(0.44 g, 95%) as a brown solid. Rf (CH2Ch/MeOH/NH4OH 90/9/1) 0.26. Mp: > 260 °C. 1H NMR (250 MHz, DMSO-de) 811.73 (brs, 1H, OH), 11.67 (s, 1H, NH), 7.74 (s, 1H, CH), 4.79 - 4.65 (m, 2H, CH2), 3.87 (t, J = 5.5 Hz, 2H, CH2), 2.66 (t, J = 5.5 Hz, 2H, CH2). HRMS (EI-MS) m/z calcd. for C9H10N3O2 [M+H]+: 192.0768, found: 192.0769.

Benzyl 4-hydroxy-5,7,8,9-tetrahydro-6H-pyrido[3',4':4,5]pyrrolo[2,3-d]pyrimidine-6-carboxylate (143)

The reaction was carried out as described in the general procedure using hydrazone 140 (0.5 g, 1.46 mmol) in tetralin (10 mL). The precipitate was filtered and washed several times with PE (3 x 10 mL) and Et O (10 mL) to afford compound 143 (0.45 g, 94%) as a beige solid. Rf (CH Ch / MeOH / NH OH 90/9/1) 0.42. Mp: > 260 °C. 1H NMR (250 MHz, DMSO-de) 811.76 (brs, 1H, OH), 11.70 (s, 1H, NH), 7.75 (s, 1H, H2), 7.45 - 7.26 (m, 5H, 5xH), 5.12 (s, 2H, OCH2), 4.61 (s, 2H, CH2(5)), 3.73 (t, J = 5.8 Hz, 2H, CH2(7)), 2.68 (t, J = 5.7 Hz, 2H, CH2(8)). HRMS (EI-MS) m/z calcd. for C17H17N4O3 [M+H]+: 325.1295, found: 325.1294.

4-chloro-5,7,8,9-tetrahydrothiopyrano[3',4':4,5]pyrrolo[2,3-d]pyrimidine (144)

The reaction was carried out as described in the general procedure by taking tricycle 141 (1.0 g, 4.83 mmol) in POCl 3 (35 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch / acetone from 100/0 to 70/30 to afford compound 144 (0.74 g, 68%) as a beige solid. Rf (CH 2 Cfc / acetone 60/40) 0.28. Mp: > 260 °C. 1H NMR (250 MHz, DMSO-de) 812.34 (brs, 1H, NH), 8.46 (s, 1H, CH), 3.95 (s, 2H, CH 2 ), 3.03 - 2.92 (m, 4H, 2 x CH 2 ). HRMS (EI-MS) m/z calcd. for C9H9ClN3S [M+H]+: 226.0200, found: 226.0200.

4-chloro-5,7,8,9-tetrahydropyrano[3',4':4,5]pyrrolo[2,3-d]pyrimidine (145)

In a round-bottom flask, 142 (0.2 g, 1.05 mmol) was suspended in CHCl (4 mL) and treated with 2 drops of N,N-dimethylformamide and oxalyl chloride (0.4 mL, 4.73 mmol, 4.5 equiv.). The reaction mixture was heated at reflux for 5 h. The solvent was removed under reduced pressure, the residue was dissolved in CH Cl (100 mL) and shaken with saturated aqueous Na CO (50 mL). The organic phase was dried over MgSO , filtered, and concentrated under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Ch/acetone from 100/0 to 50/50 to afford compound145 (65 mg, 30%) as a beige solid. Rf(CH2Ch/acetone 70/30) 0.34. Mp: > 260 °C. 1H NMR (250 MHz, DMSO-de) 8 12.43 (s, 1H, NH), 8.79 - 8.13 (m, 1H, CH), 5.07 - 4.76 (m, 2H, CH2), 3.96 (t, J = 5.4 Hz, 2H, CH2), 2.90 - 2.75 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for CgHgClNsO [M+H]+: 210.0429, found: 210.0428.

Benzyl 4-chloro-5,7,8,9-tetrahydro-6H-pyrido[3',4':4,5]pyrrolo[2,3-d]pyrimidine-6-carboxylate hydrochloride (146)

The reaction was carried out as described in the general procedure using tricycle 143 (1.0 g, 3.08 mmol) in POCla (25 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch / acetone from 80/20 to 20/80 to afford compound 146 (0.62 g, 53%) as a white solid. Rf (CH 2 Ch / acetone 60/40) 0.31. Mp: 180 - 182 °C. 1H NMR (250 MHz, DMSO-de) 812.45 (s, 1H, NH), 8.48 (s, 1H, CH), 7.52 - 7.22 (m, 5H, 5 x CH), 5.14 (s, 2H, OCH2), 5.00 (brs, 1H, H+), 4.87 - 4.64 (m, 2H, CH2), 3.93 - 3.69 (m, 2H, CH2), 2.91 - 2.78 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for C17H17ClN4O2 [M+H]+: 343.0956, found: 343.0954.

4-chloro-6-methyl-6,7,8,9-tetrahydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-d]pyrimidine (147)

In a round-bottom flask, 146 (2.3 g, 6.71 mmol) was dissolved in anhydrous THF (90 mL) under argon and the solution was cooled to 0 °C over 10 min. Then, L¡AlH4 (1.27 g, 33.55 mmol, 5.0 equiv.) was slowly added, the mixture was stirred at 0 °C for an additional 10 min and 2 h at room temperature. Water (2 mL), 2 M aqueous NaOH solution (2 mL) and H2O (2 mL) were successively added dropwise to the mixture. The precipitate was filtered on a pad of Celite and washed with MeOH (50 mL). The solvent was removed under reduced pressure and the crude reaction mixture was purified by column chromatography on silica gel using a gradient solvent system of CH2Cl2/MeOH from 95/5 to 85/15 to afford compound147 (1.18 g, 79%) as a white solid. Rf (CH2Ch/MeOH 90/10) 0.17. Mp: 250 - 252 °C. 1H NMR (250 MHz, MeOD-d4) 88.42 (s, 1H, CH), 3.86 - 3.82 (m, 2H, CH2), 2.99 - 2.85 (m, 4H, 2 x CH2), 2.57 (s, 3H, NCH3). HRMS (EI-MS) m/z calcd. for C10H12ClN4 [M+H]+: 223.0745, found: 223.0745.

4-(5,7,8,9-tetrahydrothiopyrano[3',4':4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester (148)

The reaction was carried out as described in the general procedure using chlorinated tricycle 144 (0.35 g, 1.55 mmol) and N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (0.52 g, 1.71 mmol, 1.1 equiv.) in THF (9 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch /acetone from 90/10 to 40/60 to provide compound 148 (0.49 g, 85%) as a white solid. Rf (CH 2 Ch /acetone 80/20) 0.21. Mp: 211 - 213 °C 1H NMR (250 MHz, MeOD-d4) 88.57 (s, 1H, CH), 6.06 - 5.95 (m, 1H, CH), 4.21 - 4.10 (m, 2H, CH2), 3.76 - 3.66 (m, 4H, 2 x CH2), 3.10 -2.93 (m, 4H, 2 x CH2), 2.69 - 2.56 (m, 2H, CH2), 1.51 (s, 9H, 3 x CH3). HRMS (EI-MS) m/z calcd. for C19H25N4O2S [M+H]+: 373.1693, found: 373.1693.

4-(5,7,8,9-tetrahydropyrano[3',4':4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester (149)

The reaction was carried out as described in the general procedure using chlorinated tricycle 145 (0.35 g, 1.67 mmol) and N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (0.57 g, 1.84 mmol, 1.1 equiv.) in THF (9 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch / acetone from 90/10 to 60/40 to provide compound 149 (0.53 g, 89%) as a white solid. Rf (CH 2 Ch / acetone 80/20) 0.27. Mp: 236 - 238 °C. 1H NMR (250 MHz, DMSO-de) 812.02 (s, 1H, NH), 8.61 (s, 1H, CH), 6.11 - 5.94 (m, 1H, CH), 4.67 (s, 2H, CH2), 4.11 - 4.00 (m, 2H, CH2), 4.01 - 3.90 (m, 2H, CH2), 3.63 - 3.50 (m, 2H, CH2), 2.89 - 2.79 (m, 2H, CH2), 2.64 - 2.56 (m, 2H, CH2), 1.45 (s, 9H, 3 x CH3). HRMS (EI-MS) m/z calcd. for C19H25N4O3 [M+H]+: 357.1921, found: 357.1921.

4-(6-methyl-6,7,8,9-tetrahydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester (150)

The reaction was carried out as described in the general procedure using chlorinated tricycle 147 (0.35 g, 1.58 mmol) and N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (0.54 g, 1.73 mmol, 1.1 equiv.) in THF (9 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch / acetone/NH 4 OH from 70/28/2 to 0/98/2. After evaporation, the product was dissolved in CH 2 Cl 2 (20 mL), the pH was adjusted to 7 by the addition of 1 M aqueous HCl solution. The organic layer was separated, dried over MgSO4, filtered, and concentrated in vacuo to afford compound 150 (0.46 g, 79%) as a pink solid. Rf (CH2Ch/acetone/NH4OH 70/28/2) 0.18. Mp: 210 - 212 °C. 1H NMR (250 MHz, DMSO-de) 811.90 (s, 1H, NH), 8.57 (s, 1H, CH), 6.09 - 5.96 (m, 1H, CH), 4.05 (s, 2H, CH2), 3.57 (t, J = 5.4 Hz, 2H, CH2), 3.40 (s, 2H, CH2), 2.86 - 2.77 (m, 2H, CH2), 2.75 - 2.65 (m, 2H, CH2), 2.63 - 2.54 (m, 2H, CH2), 2.39 (s, 3H, NCH3), 1.44 (s, 9H, 3 x CH3). HRMS (EI-MS) m/z calcd. for C20H28N5O2 [M+H]+: 370.2238, found: 370.2236.

4-(1,2,3,6-tetrahydropyridin-4-yl)-5,7,8,9-tetrahydrothiopyrano[3',4':4,5]pyrrolo[2,3-d]pyrimidine (151)

The reaction was carried out as described in General Procedure F1 using the N-Boc protected compound 148 (1.0 g, 2.68 mmol) in CH 2 Cl 2 (80 mL). The reaction was complete after 1 h. Work-up gave compound 151 (0.56 g, 98%) as a beige solid. Mp: 241 - 243 °C. 1H R<m>N (250 MHz, MeOD-d4) 88.56 (s, 1H, CH), 6.01 (tt, J = 3.2, 1.8 Hz, 1H, CH), 3.83 - 3.74 (m, 2H, CH2), 3.53 (dt, J = 2.9 Hz, J = 2.9 Hz, 2H, CH2), 3.10 (t, J = 5.7 Hz, 2H, CH2), 3.08 - 2.95 (m, 4H, 2 x CH2), 2.63 - 2.51 (m, 2H, CH2). HRMS (EI-MS): m/z calcd. for C14H17N4 S [M+H]+: 273.1168, found: 273.1168.

4-(1,2,3,6-tetrahydropyridin-4-yl)-5,7,8,9-tetrahydropyran[3',4':4,5]pyrrolo[2,3-d]pyrimidine (152)

The reaction was carried out as described in General Procedure F1 using the N-Boc protected compound 149 (1.0 g, 2.81 mmol) in CH 2 Cl 2 (80 mL). The reaction was complete after 1 h. Work-up gave compound 152 (0.60 g, 83%) as an off-white solid. Mp: 231 - 233 °C. 1H NMR (250 MHz, DMSO-d6) 8 12.01 (brs, 1H, NH), 8.59 (s, 1H, CH), 6.07 - 5.97 (m, 1H, CH), 4.72 - 4.62 (m, 2H, CH2), 3.95 (t, J = 5.6 Hz, 2H, CH2), 3.52 - 3.45 (m, 2H, CH2), 3.02 (t, J = 5.7 Hz, 2H, CH2), 2.88 - 2.76 (m, 2H, CH2), 2.58 - 2.47 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for C14H17N4 O[M+H]+: 257.1397, found: 257.1396.

6-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)-6,7,8,9-tetrahydro-5H-pyrido[3',4':4,5]pyrrolo[2,3-d]pyrimidine (153)

The reaction was carried out as described in general procedure F1 using the N-Boc protected compound 150 (1.0 g, 2.71 mmol) in CH 2 Cl 2 (80 mL). The reaction was complete after 1 h. Work-up gave compound 153 (0.61 g, 84%) as a beige solid. Mp: degradation 226 °C. 1H NMR (250 MHz, MeOD-d4) 8 8.58 (s, 1H, CH), 6.11 - 6.04 (m, 1H, CH), 3.69 - 3.57 (m, 4H, 2 x CH2), 3.21 (t, J = 5.8 Hz, 2H, CH2), 3.04 - 2.86 (m, 4H, 2 x CH2), 2.72 - 2.63 (m, 2H, CH2), 2.54 (s, 3H, NCH3). HRMS (EI-MS) m/z calcd. for C15H20N5 [M+H]+: 270.1713, found: 270.1713.

Example 85: N-(3-fluorophenyl)-4-(5,7,8,9-tetrahydrothiopyrano[3',4':4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3 ,6-dihydropyridine-1(2H)-carboxamide (154)

The reaction was carried out as described in the general procedure by using amine 151 (70 mg, 0.26 mmol) in anhydrous CH 2 Cl 2 (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch / acetone from 90/10 to 20/80 to provide compound 154 (86 mg, 83%) as a beige solid. Rf (CH 2 Ch / acetone 40/60) 0.27. Mp: degradation 200 °C. 1H NMR (400 MHz, DMSO-de) 811.96 (brs, 1H, NH), 8.77 (brs, 1H, NH), 8.61 (s, 1H, CH), 7.48 (d, J = 12.3 Hz, 1H, CH), 7.35 - 7.22 (m, 2H, 2 x CH), 6.75 (t, J = 8.3 Hz, 1H, CH), 6.13 - 5.99 (m, 1H, CH), 4.27 - 4.17 (m, 2H, CH2), 3.84 - 3.65 (m, 4H, 2 x CH2), 3.05 - 2.91 (m, 4H, 2 x CH2), 2.74 - 2.63 (m, 2H, CH2). 19F NMR (376 MHz, DMSO-d6) 8 -112.9 (s). HRMS (EI-MS) m/z calcd. for C21H21FN5OS [M+H]+: 410.1445, found: 410.1440.

Example 86: N-(3-chlorophenyl)-4-(5,7,8,9-tetrahydrothiopyrano[3',4':4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3 ,6-dihydropyridine-1(2H)-carboxamide (155)

The reaction was carried out as described in the general procedure by using amine 151 (70 mg, 0.26 mmol) in anhydrous CH 2 Cl 2 (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch / acetone from 80/20 to 10/90 to afford compound 155 (89 mg, 81%) as a brown solid. Rf (CH 2 Ch / acetone 40/60) 0.28. Mp: degradation 206 °C. 1H NMR (250 MHz, MeOD-d4) 88.59 (s, 1H, CH), 7.74 - 7.67 (m, 1H, CH), 7.42 - 7.33 (m, 1H, CH), 7.23 - 7.12 (m, 2H, 2 x CH), 6.06 (s, 2H, CH), 4.33 - 4.24 (m, 2H, CH2), 3.82 (t, J = 5.6 Hz, 2H, CH2), 3.77 (s, 2H, CH2), 3.11 -2.96 (m, 4H, 2 x CH2), 2.73 (s, 2H, CH2). HRMS (EI-MS) m/z calcd. for C21H21ClNsOS [M+H]+: 426.1150, found: 426.1147.

Example_____87. N-(3-bromophenyl)-4-(5,7,8,9-tetrahydrothiopyrano[3',4':4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,6- dihydropyridine-1(2H)-carboxamide (156)

The reaction was carried out as described in the general procedure by using amine 151 (70 mg, 0.26 mmol) in anhydrous CH 2 Cl 2 (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch / acetone from 80/20 to 10/90 to afford compound 156 (99 mg, 82%) as a brown solid. Rf (CH 2 Ch / acetone 40/60) 0.28. Mp: degradation 220 °C. 1H NMR (250 MHz, MeOD-d4) 88.61 (s, 1H, CH), 7.56 (d, J = 2.2 Hz, 1H, CH), 7.32 (d, J = 8.4 Hz, 1H, CH), 7.24 (t, J = 8.0 Hz, 1H, CH), 7.01 (d, J = 7.7 Hz, 1H, CH), 6.12 - 6.04 (m, 1H, CH), 4.34 - 4.24 (m, 2H, CH2), 3.83 (t, J = 5.6 Hz, 2H, CH2), 3.77 (s, 2H, CH2), 3.12 - 2.93 (m, 4H, 2 x CH2), 2.79 - 2.67 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for C21H21BrNsOS [M+H]+: 470.0645, found: 470.0639.

Example 88: W-(3-fluorophen¡l)-4-(5,7,8,9-tetrah¡drop¡rane[3',4':4,5]pyrrolo[2,3-d] p¡r¡m¡d¡n-4-¡l)-3,6-di¡hydropyr¡d¡n-1(2H)-carboxamide (157)

The reaction was carried out as described in the general procedure by using amine 152 (60 mg, 0.16 mmol) in anhydrous CH 2 Cl 2 (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch / acetone from 80/20 to 20/80 to provide compound 157 (42 mg, 67%) as a beige solid. Rf (CH 2 Ch / acetone 50/50) 0.25. Mp: 223 - 225 °C. 1H NMR (400 MHz, DMSO-de) 812.02 (brs, 1H, NH), 8.78 (brs, 1H, NH), 8.62 (s, 1H, CH), 7.48 (dt, J = 12.3 Hz, J = 2.2 Hz, 1H, CH), 7.32 - 7.21 (m, 2H, 2 x CH), 6.79 - 6.71 (m, 1H, CH), 6.11 - 6.06 (m, 1H, CH), 4.69 (s, 2H, CH2), 4.30 - 4.14 (m, 2H, CH2), 3.96 (t, J = 5.6 Hz, 2H, CH2), 3.71 (t, J = 5.6 Hz, 2H, CH2), 2.86 - 2.78 (m, 2H, CH2), 2.71 - 2.62 (m, 2H, CH2). 19F NMR (376 MHz, DMSO-d6) 8 -112.9 (s). HRMS (EI-MS) m/z calcd. for C21H21 FN5O2 [M+H]+: 394.1674, found: 394.1673.

Example 89: W-(3-chlorophen¡l)-4-(5,7,8,9-tetrahydro¡drop¡rane[3',4':4,5]pyrrole[2,3-d] p¡r¡m¡d¡n-4-¡l)-3,6-di¡hydropyr¡d¡n-1(2H)-carboxamide (158)

The reaction was carried out as described in the general procedure by using amine 152 (60 mg, 0.16 mmol) in anhydrous CH 2 Cl 2 (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch / acetone from 80/20 to 20/80 to provide compound 158 (47 mg, 72%) as a beige solid. Rf (CH 2 Ch / acetone 50/50) 0.28. Mp: 224 - 226 °C. 1H NMR (400 MHz, DMSO-de) 8 12.03 (brs, 1H, NH), 8.76 (brs, 1H, NH), 8.62 (s, 1H, CH), 7.69 (t, J = 2.2 Hz, 1H, CH), 7.44 (dd, J = 8.2 Hz, J = 2.1 Hz, 1H, CH), 7.26 (t, J= 8.1 Hz, 1H, CH), 6.98 (dd, J = 7.8 Hz, J = 2.1 Hz, 1H, CH), 6.13 - 6.06 (m, 1H, CH), 4.69 (s, 2H, CH2), 4.26 - 4.17 (m, 2H, CH2), 3.96 (t, J = 5.6Hz, 2H, CH2), 3.71 (t, J = 5.6 Hz, 2H, CH2), 2.86 - 2.79 (m, 2H, CH2), 2.73 - 2.62 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for C21H21ClNeO2 [M+H]+: 410.1378, found: 410.1377.

Example 90: W-(3-bromophen¡l)-4-(5,7,8,9-tetrah¡drop¡rane[3',4':4,5]p¡rrolo[2,3-d] p¡r¡m¡d¡n-4-¡l)-3,6-d¡hydropyr¡d¡n-1(2H)-carboxamide (159)

The reaction was carried out as described in the general procedure by taking the amine 152 (60 mg, 0.16 mmol) in anhydrous CH 2 Cl 2 (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch / acetone from 80/20 to 20/80 to provide compound 159 (52 mg, 71%) as a beige solid. Rf (CH 2 Ch / acetone 50/50) 0.27. Mp: 219 - 221 °C. 1H NMR (400 MHz, DMSO-de) 8 12.03 (brs, 1H, NH), 8.74 (brs, 1H, NH), 8.62 (s, 1H, CH), 7.83 (t, J = 2.1 Hz, 1H, CH), 7.49 (dd, J = 8.1 Hz, J= 2.0 Hz, 1H, CH), 7.20 (t, J= 8.0 Hz, 1H, CH), 7.11 (dd, J = 7.9 Hz, J = 1.9 Hz, 1H, CH), 6.13 - 6.04 (m, 1H, CH), 4.69 (s, 2H, CH2), 4.25 - 4.16 (m, 2H, CH2), 3.96 (t, J= 5.5Hz, 2H, CH2), 3.71 (t, J = 5.6 Hz, 2H, CH2), 2.83 (t, J = 5.5 Hz, 2H, CH2), 2.71 - 2.63 (m, 2H, CH2). HRMS (EI-MS) m/z calcd. for C21H21BrNeO2 [M+H]+: 454.0873, found: 454.0870.

Example__________ 91 W-(3-fluorophen¡l)-4-(6-methyl-6,7,8,9-tetrahydro-5H-pyr¡do[3',4':4,5 ]pyrrolo[2,3-d]p¡r¡m¡d¡n-4-¡l)-3,6-dih¡drop¡rid¡n-1(2H)-carboxam¡de (160)

The reaction was carried out as described in the general procedure by taking the amine 153 (40 mg, 0.15 mmol) in anhydrous CH 2 Cl 2 (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch / MeOH from 98/2 to 82/18 to provide compound 160 (41 mg, 68%) as a beige solid. Rf (CH 2 Ch / MeOH 85/15) 0.16. Mp: degradation 191 °C1H NMR (400 MHz, DMSO-de) 812.25 (brs, 1H, NH), 8.90 (brs, 1H, NH), 8.67 (s, 1H, CH), 7.51 (d, J = 12.3 Hz, 1H, CH), 7.39 - 7.16 (m, 2H, 2 x CH), 6.75 (t, J = 8.6 Hz, 1H, CH), 6.19 - 6.00 (m, 1H, CH), 4.26 (s, 2H, CH2), 4.11 (s, 2H, CH2), 3.75 (s, 2H, CH2), 3.40 - 3.28 (m, 2H, CH2), 3.07 (s, 2H, CH2), 2.80 (s, 3H, NCH3), 2.71 (s, 2H, CH2). 19F NMR (376 MHz, DMSO-d6) 8 -112.9 (s). HRMS (EI-MS) m/z calcd. for C22H24FN6O [M+H]+: 407.1990, found: 407.1988.

Example__________ 92: W-(3-chlorophen¡l)-4-(6-methyl-6,7,8,9-tetrahydro-5H-pyr¡do[3',4':4, 5]pyrrolo[2,3-d]pyr¡m¡din-4-¡l)-3,6-dih¡drop¡rid¡n-1(2H))-carboxamide (161)

The reaction was carried out as described in the general procedure by using amine 153 (70 mg, 0.26 mmol) in anhydrous CH 2 Cl 2 (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch / MeOH from 98/2 to 82/18 to afford compound 161 (58 mg, 53%) as a beige solid. R f (CH 2 Cfc / MeOH 85/15) 0.16. Mp: degradation 193 °C. 1H NMR (400 MHz, DMSO-de) 812.21 (brs, 1H, NH), 8.93 (brs, 1H, NH), 8.65 (s, 1H, CH), 7.73 (s, 1H, CH), 7.49 (d, J = 8.4 Hz, 1H, CH), 7.26 (t, J = 8.1 Hz, 1H, CH), 6.98 (d, J = 8.1 Hz, 1H, CH), 6.13 - 6.05 (m, 1H, CH), 4.26 (s, 2H, CH2), 3.99 (s, 2H, CH2), 3.79 - 3.70 (m, 2H, CH2), 3.28 - 3.16 (m, 2H, CH2), 3.04 (s, 2H, CH2), 2.78 - 2.64 (m, 5H, NCH3 CH2). HRMS (EI-MS) m/z calcd. for C22H24ClN6O [M+H]+: 423.1695, found: 423.1694.

Example_________ 93: W-(3-bromophen¡l)-4-(6-met¡l-6,7,8,9-tetrahydro-5H-p¡r¡do[3',4':4, 5]pyrrolo[2,3-d]p¡r¡m¡d¡n-4-¡l)-3,6-dih¡drop¡rid¡n-1(2H))-carboxam¡de (162)

The reaction was carried out as described in the general procedure by using amine 153 (70 mg, 0.26 mmol) in anhydrous CH 2 Cl 2 (3 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Cl 2 /MeOH from 98/2 to 82/18 to afford compound 162 (61 mg, 50%) as a beige solid. Rf (CH 2 Cl 2 /MeOH 85/15) 0.17. Mp: degradation 191 °C. 1H NMR (400 MHz, DMSO-d6) 512.05 (brs, 1H, NH), 8.90 (brs, 1H, NH), 8.61 (s, 1H, CH), 7.87 (s, 1H, CH), 7.54 (d, J = 8.5 Hz, 1H, CH), 7.20 (t, J = 8.0 Hz, 1H, CH), 7.11 (d, J = 8.0 Hz, 1H, CH), 6.14 - 6.05 (m, 1H, CH), 4.23 (s, 2H, CH2), 3.79 - 3.58 (m, 4H, 2 x CH2), 2.90 (s, 4H, 2 x CH2), 2.72 - 2.62 (m, 2H, CH2), 2.50 (s, 3H, NCH3). HRMS (EI-MS) m/z calcd. for C22H24BrNaO [M+H]+: 467.1189, found: 467.1183.

Family 8.

Fluorescent probes synthesized from LIMK/Rock inhibitors for cellular testing

W-[3-[3-(3-aminophenyl)phenoxy]propyl]carbamate tert-butyl ester (163)

Compound 37 (377 mg, 1.01 mmol) was suspended in 30 mL of EtOAc in a hydrogenation reactor. Then, Pd/C (11 mg, 0.10 mmol, 0.1 equiv.) was added and the reaction was stirred under 10 bar of hydrogen for 48 h. The reaction mixture was then filtered over Celite and concentrated under reduced pressure to give compound 163 as a yellow oil (0.345 g, qty) which was used in the next step without further purification. Rf (EP/Et2O 80/20) 0.11. 1H NMR (400 MHz, MeOD-cf4) 57.29 (t, J= 7.9 Hz, 1H, CH), 7.18 - 7.07 (m, 3H, CH), 6.98 (t, J = 1.8 Hz, 1H, CH), 6.95 - 6.90 (m, 1H, CH), 6.89 - 6.85 (m, 1H, CH), 6.73 - 6.67 (m, 1H, CH), 4.03 (t, J = 6.3 Hz, 2H, CH2), 3.23 (q, J = 6.3 Hz 2H, CH2), 1.93 (p, J = 6.3 Hz, 2H, CH2), 1.44 (s, 9H, 3 x CH3). HRMS (EI-MS) m/z calcd. for C20H27N2O3 [M+H]+: 343.2016, found: 343.2011.

(3-((3'-(4-(5,6,7,8-tetrahydrocyclopenta[4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-1,2,3,6-tetrahydropyridin tert-butyl -1-carboxamido)-[1,1'-biphenyl]-3-yl)oxy)propyl)carbamate (164)

The reaction was carried out as described in the general procedure using compound 163 (309 mg, 0.90 mmol) and amine 107.HCl (300 mg, 1.08 mmol, 1.2 equiv.) in THF (13 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Cl 2 /acetone from 90/10 to 50/50 to provide compound 164 (350 mg, 64%) as a beige solid. Rf (CH 2 Cl 2 /acetone 50/50) 0.41. Mp: degradation 120 °C. 1H NMR (400 MHz, DMSO-d?) 511.96 (s, 1H, NH), 8.64 (s, 1H, NH), 8.58 (s, 1H, CH), 7.80 (t, J = 1.88 Hz, 1H, CH), 7.59 - 7.54 (m, 1H, CH), 7.40 - 7.29 (m, 2H, CH), 7.27 - 7.21 (m, 1H, CH), 7.20 - 7.16 (m, 1H, CH), 7.14 - 7.10 (m, 1H, CH), 6.96 - 6.88 (m, 2H, CH NH), 6.66 - 6.56 (m, 1H, CH), 4.28 (d, J = 3.0 Hz, 2H, CH2), 4.04 (t, J = 6.3 Hz, 2H, CH2), 3.73 (t, J = 5.6 Hz, 2H, CH2), 3.11 (q, J = 6.6 Hz, 2H, CH2), 2.95 - 2.83 (m, 4H, 2 x CH2), 2.79 - 2.72 (m, 2H, CH2), 2.43 (p, J = 7.28 Hz, 2H, CH2), 1.86 (p, J = 6.6 Hz, 2H, CH2), 1.37 (s, 9H, 3 x CH3). HRMS (EI-MS) m/z calcd. for C35H41N6O4 [M+H]+: 609.3184, found: 609.3180.

N-[3-[3-[3-[[4-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydro-2H-pyridine-1-carbonyl tert-butyl ]amino]phenyl]phenoxy]propyl]carbamate (165)

The reaction was carried out as described in the general procedure using compound 163 (210 mg, 0.61 mmol) and amine 70.HCl (205 mg, 0.74 mmol, 1.2 equiv.) in THF (13 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Ch /acetone from 90/10 to 50/50 to provide compound 165 (152 mg, 41%) as a beige solid.

Rf(CH2Cl2/acetone 50/50) 0.36. Mp: degradation 113 °C. 1H NMR (400 MHz, DMSO-de) 811.84 (s, 1H, NH), 8.65 (s, 2H, NH CH), 7.80 (s, 1H, CH), 7.55 (d, J = 8.0 Hz, 1H, CH), 7.40 - 7.29 (m, 2H, CH), 7.26 - 7.22 (m, 2H, 2 x CH), 7.18 (d, J = 7.8 Hz, 1H, CH), 7.12 (s, 1H, CH), 6.96 - 6.86 (m, 2H, NH CH), 6.32 - 6.26 (m, 1H, CH), 4.30 - 4.20 (m, 2H, CH2), 4.04 (t, J = 6.3 Hz, 2H, CH2), 3.77 (t, J = 5.6 Hz, 2H, CH2), 3.11 (q, J = 6.5 Hz, 2H, CH2), 2.81 - 2.66 (m, 2H, CH2), 1.93 - 1.80 (m, 3H, CH CH2), 1.37 (s, 9H, 3 x CH3), 0.86 - 0.76 (m, 2H, CH2), 0.66 - 0.57 (m, 2H, CH2). HRMS (EI-Ms ) m/z calcd. for C35H41N6O4[M+H]+: 609.3184, found: 609.3180.

W-[3-[3-[3-[[4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydro-2H-pyridine-1-carbonyl tert-butyl ]amino]phenyl]phenoxy]propyl]carbamate (166)

The reaction was carried out as described in the general procedure using compound 163 (300 mg, 0.88 mmol) and amine 4 (263 mg, 1.05 mmol, 1.2 equiv.) in THF (13 mL). The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH 2 Cl 2 /acetone from 90/10 to 50/50 to provide compound 166 (294 mg, 58%) as a beige solid. Rf (CH 2 Cl 2 /acetone 50/50) 0.32. Mp: degradation 105 °C. 1H NMR (250 MHz, DMSO-de) 811.83 (s, 1H, NH), 8.67 (s, 1H, NH), 8.65 (s, 1H, CH), 7.81 (s, 1H, CH), 7.57 (d, J = 7.9 Hz, 1H, CH), 7.42 - 7.08 (m, 6H, 6 x CH), 6.97 - 6.84 (m, 2H, CH NH), 6.06 (s, 1H, CH), 4.35 - 4.20 (m, 2H, CH2), 4.04 (t, J = 6.0 Hz, 2H, CH2), 3.76 (t, J = 5.5 Hz, 2H, CH2), 3.21 - 3.02 (m, 2H, CH2), 2.77 - 2.63 (m, 2H, CH2), 2.25 (s, 3H, CH3), 1.87 (p, J = 6.6 Hz, 2H, CH2), 1.37 (s, 9H, 3 x CH3). HRMS (EI-MS) m/z calcd. for C33H39N6O4 [M+H]+: 583.3027, found: 583.3018.

W-(3'-(3-(3-(5,5-difluoro-7,9-dimethyl-5H-dipyrrolo[1,2-c:2',1'-/ ][1,3,2]d¡azabonn¡n-3-¡l)propanam¡do)propoxy¡)-[1,1'-biphen¡l]-3-yl)-4-(5, 6,7,8-tetrahydro cyclopenta[4,5]pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H)-carboxamide (167)

A solution of HCl (4 N in dioxane, 0.164 mL, 8 equiv.) was slowly added to a solution of urea (50 mg, 0.08 mmol) in CH Cl (3 mL) at 0 °C and stirred at room temperature until the reaction was complete by TLC. The solvent was then evaporated under reduced pressure and the crude amine salt was used in the next step without further purification. Anhydrous M (10 mL) was added and the reaction was placed under Ar. DIPEA (0.086 mL, 0.49 mmol, 6.0 equiv.), HOBt (33 mg, 0.25 mmol, 3.0 equiv.) and 3-(5,5-Difluoro-7,9-dimethyl-5H-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinin-3-yl)propanoic acid (26 mg, 0.09 mmol, 1.1 equiv.) were then added followed by EDC (38 mg, 43 µl, 0.25 mmol, 3.0 equiv.). The reaction was stirred at rt overnight. The reaction mixture was diluted with water (3 mL) and the aqueous layer was extracted with AcOEt (3 x 10 mL). The combined organic layers were washed with brine, dried over MgSO4 and the solvent was removed under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Ch/acetone from 100/0 to 70/30 to afford compound167 (16 mg, 25%) as a red solid. Rf (CH2Ch/acetone 50/50) 0.18. Mp: degradation 103 °C. 1H NMR (400 MHz, CDCla) 8 (ppm) 9.63 (s, 1H, NH), 8.71 (s, 1H, CH), 7.57 (s, 1H, CH), 7.53 - 7.47 (m, 1H, CH), 7.34 (t, J = 7.9 Hz, 1H, CH), 7.29 - 7.23 (m, 2H, 2 x CH), 7.19 - 7.14 (m, 1H, CH), 7.06 -7.03 (m, 1H, CH), 6.94 (s, 1H, CH), 6.82 - 6.78 (m, 2H, NH CH), 6.76 (d, J = 3.9 Hz, 1H, CH), 6.54 - 6.50 (m, 1H, CH), 6.24 (d, J = 4.0 Hz, 1H, CH), 6.14 (t, J = 5.7 Hz, 1H, NH), 6.06 (s, 1H, CH), 4.30 (d, J = 3.0 Hz, 2H, CH2), 3.93 (t, J = 6.1 Hz, 2H, CH2), 3.79 (t, J= 5.6 Hz, 2H, CH2), 3.42 (q, J = 6.2 Hz, 2H, CH2), 3.27 (t, J = 7.4 Hz, 2H, CH2), 2.95 (t, J = 7.2 Hz, 2H, CH2), 2.92 - 2.83 (m, 4H, 2 x CH2), 2.66 (t, J = 7.3 Hz, 2H, CH2), 2.58 - 2.43 (m, 5H, CH2 CH3), 2.17 (s, 3H, CH3), 1.92 (p, J = 6.3 Hz, 2H, CH2). HRMS (EI-MS) m/z calcd. for C44H46BF2N8O3 [M+H]+: 783.3749, found: 783.3754.

W-(3'-(3-(3-(5,5-difluoro-7,9-dimethyl-5H-dipyrrolo[1,2-c:2',1'-/][1,3,2] diazaborinin-3-yl)propanamido)propox i)-[1,1'-biphenyl]-3-yl)-4-(5-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1(2H )-carboxamide (168)

A solution of HCl (4 N in dioxane, 0.26 mL, 8 equiv.) was slowly added to a solution of urea (81 mg, 0.13 mmol) in CH Cl 2 (3 mL) at 0 °C and stirred at room temperature until the reaction was complete by TLC. The solvent was then evaporated under reduced pressure and the crude amine salt was used in the next step without further purification. Anhydrous M (10 mL) was added and the reaction was placed under Ar. DIPEA (0.140 mL, 0.80 mmol, 6.0 equiv.), HOBt (54 mg, 0.40 mmol, 3.0 equiv.) and 3-(5,5-Difluoro-7,9-dimethyl-5H-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborin-3-yl)propanoic acid (43 mg, 0.15 mmol, 1.1 equiv.) were then added followed by EDC (71.2 µl, 0.40 mmol, 3.0 equiv.). The reaction was stirred at rt overnight. The reaction mixture was diluted with water (3 mL) and the aqueous layer was extracted with AcOEt (3 x 10 mL). The combined organic layers were washed with brine, dried over MgSO4 and the solvent was removed under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH2Ch/MeOH from 100/0 to 90/10 to afford compound168 (25 mg, 24%) as a red solid. Rf (CH2Ch/acetone 90/10) 0.52. Mp: degradation 138 °C. 1H NMR (250 MHz, CDCb) 810.18 (brs, 1H, NH), 8.80 (s, 1H, CH), 7.60 - 7.54 (m, 1H, CH), 7.50 (d, J = 8.0 Hz, 1H, CH), 7.33 (t, J = 7.8 Hz, 1H, CH), 7.26 (t, J = 7.9 Hz, 2H, 2 x CH), 7.15 (d, J = 7.8 Hz, 1H, CH), 7.04 - 7.01 (m, 1H, CH), 7.01 - 6.95 (m, 2H, CH NH), 6.94 (s, 1H, CH), 6.82 - 6.73 (m, 2H, 2 x CH), 6.28 - 6.15 (m, 3H, 2 x CH, NH), 6.05 (s, 1H, CH), 4.32 - 4.18 (m, 2H, CH2), 3.91 (t, J = 6.1 Hz, 2H, CH2), 3.82 (t, J = 5.5 Hz, 2H, CH<2>), 3.41 (q,J = 6.3 Hz, 2H,CH<2>), 3.26 (t, J= 7.3 Hz, 2H, CH<2>), 2.84 (s, 2H, CH<2>), 2.65 (t,J =7.3 Hz, 2H, CH<2>), 2.48 (s, 3H, CH<3>), 2.16 (s, 3H, CH<3>), 1.91 (p, J = 6.0 Hz, 2H, CH<2>), 1.85 - 1.74 (m, 1H, CH), 0.91 - 0.78 (m, 2H, CH<2>), 0.62 - 0.51 (m, 2H, CH<2>). HRMS (EI-MS) m/z calcd. for C<44>H<46>BF<2>N<8>O<3>[M+H]<+>: 783.3749, found: 783.3755.

W-(3'-(3-(3-(5,5-difluoro-7,9-dimethyl-5H-dipyrrolo[1,2-c:2',1' -f][1,3,2]d¡azabor¡n¡n-3-¡l)propanam¡do)pro pox¡H1,1'-biphen¡l]-3-¡l)-4-(5-met¡l-7H-p¡rrolo[2,3-d]p¡r¡m¡d¡n -4-¡l)-3,6-di¡hydro¡r¡dina-1(2H)-carboxamide (169)

A solution of HCl (4 N in dioxane, 0.34 mL, 8 equiv.) was slowly added to a solution of urea (100 mg, 0.17 mmol) in CH<2>Cl<2> (4 mL) at 0 °C and stirred at rt until the reaction was complete by TLC. The solvent was then evaporated under reduced pressure and the crude amine salt was used in the next step without further purification. Anhydrous DMF (12 mL) was added and the reaction was placed under Ar. DIPEA (0.18 ml, 1.03 mmol, 6.0 equiv.), HOBt (70 mg, 0.52 mmol, 3.0 equiv.) and acid were then added. 3-(5,5-difluoro-7,9-dimethyl-5H-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaboran-3-l)propanoic (55 mg, 0.19 mmol, 1.1 eq.) followed by EDC (91 pl, 0.52 mmol, 3.0 equivalent). The reaction was agitated at t.a. overnight. The reaction mixture was diluted with water (4 mL) and the aqueous layer was extracted with AcOEt (3 x 15 mL). The combined organic phases were washed with brine, dried over MgSO<4> and the solvent was removed under reduced pressure. The crude reaction mixture was purified by silica gel column chromatography using a gradient solvent system of CH<2>Cl<2>/MeOH from 100/0 to 90/10 to afford compound 169 (37 mg, 28%) as a red solid. Rf(CH<2>Cl<2>/acetone 95/5) 0.25. Mp: 130 °C.<1>H NMR (400 MHz, CDCl<3>) 89.70 (s, 1H, NH), 8.80 (s, 1H, CH), 7.60 - 7.55 (m, 1H, CH), 7.52 - 7.48 (m, 1H, CH), 7.34 (t, J= 7.9 Hz, 1H, CH), 7.30 - 7.23 (m, 2H, CH), 7.19 - 7.14 (m, 1H, CH), 7.08 (brs, 1H, CH), 7.04 (t, J= 2.1 Hz, 1H, CH), 6.95 (brs, 1H, CH), 6.86 (brs, 1H, NH), 6.80 (dd, J = 8.2, 2.5 Hz, 1H, CH), 6.75 (d, J= 4.0 Hz, 1H, CH), 6.23 (d, J = 4.0 Hz, 1H, CH), 6.16 (t, J = 5.9 Hz, 1H, NH), 6.06 (s, 1H, CH), 5.99 (s, 1H, CH), 4.27 (d, J = 2.9 Hz, 2H, CH<2>), 3.93 (t, J = 6.2 Hz, 2H, CH<2>), 3.82 (t, J= 5.6 Hz, 2H, CH<2>), 3.42 (q, J = 6.3 Hz, 2H, CH<2>), 3.26 (t, J = 7.4 Hz, 2H, CH<2>), 2.87 - 2.77 (m, 2H, CH<2>), 2.65 (t, J = 7.4 Hz, 2H, CH<2>), 2.48 (s, 3H, CH<3>), 2.26 (s, 3H, CH<3>), 2.17 (s, 3H, CH<3>), 1.92 (p, J = 6.3 Hz, 2H, CH<2>). HRMS (EI-MS) m/z calcd. for C<42>H<44>BF<2>N<s>O<3>[M+H]+ 757.3593; found: 757.3592.

Biological studies

1.In vitro assay

1.1. Inhibition of LIMK1 and LIMK2

LIMK1 and LIMK2 inhibition was measured using the “Lanthascreen<®>Eu binding assay” (Life Technologies). This TR-FRET assay is based on the competition between a fluorescent tracer and the inhibitor to be analyzed, allowing the determination of an inhibition constant, K¡.

133 compounds have been tested. About a dozen of these compounds have their K¡ below 10 nM and approximately fifty below 50 nM. These results are very promising, since the K¡ values of the reference compounds LIMK1 and LX7101 are 8 and 3.9 nM, respectively, and the compound Pyr1 tested in breast cancer tumors has an IC<50>of 50 nM in LIMK1 and 75 nM in LIMK2.

1.2. Inhibition of ROCK1 and ROCK2

The inhibition of ROCK1 and ROCK2 has also been evaluated, but at a single concentration of 1 pM. These tests have been performed using the “Z'Lyte<®>” assay based on the inhibition of the phosphorylation of a reference measured by FRET (Life Technologies).

Based on this assay, the compounds were classified into two groups: (!) compounds that selectively inhibit LIMK, (!) possible “dual” compounds that inhibit both LIMK and ROCK.

1.3. Selectivity in a panel of 100 cells

The selectivity of the compounds towards LIMK1 and LIMK2 has been tested by Eurofins K¡nase Screen¡ng & Prof¡l¡ng Serv¡ces against 100 representative kinases at a concentration of 1 pM.

Eighteen compounds have been tested. 6 of them are highly selective and exclusively inhibit LIMK1 and LIMK2 by more than 80%. These compounds are good candidates for future in vivo assays. Selective compounds avoid unwanted, side effects that could be detrimental. Specifically, we want to develop compounds that do not target ROCK1 and ROCK2, the upstream kinase of LIMK1/2 that has many physiological targets. LIMK1 and LIMK2 are actually downstream of their signaling pathway, the only downstream effector is their unique substrate kinase. By selectively targeting LIMK1 and LIMK2, side effects should be avoided.

2. Cell assays

Six cell assays have been used to characterize the activity of our compounds:

1. Determination of cytotoxicity in various cell lines

2. Remodeling of the actin cytoskeleton, by measuring the level of phosphocofilin, cofilin is the canonical substrate of LIMK;

3. Actin cytoskeleton dynamics, by visualizing stress fibers induced by LIMK2 overexpression

4. Migration properties measured by wound healing assay

5. Microtubule dynamics by visualizing mitotic spindles

6. Plasticity of dendrites by measuring their size

2.1. Cytotoxicity

The cytotoxicity of our compounds was evaluated using the Promega “CellTiter-Glo<®> Luminescent Cell Viability” assay. This assay is based on the production of ATP by living cells. Two cell lines were studied; HeLa and MPNST (malignant peripheral nerve sheath tumor, tumors associated with the genetic disease neurofibromatous type I).

Day 1: Cell preparation in 96-well plates

Seed HeLa cells at 10,000 cells per well in 100 µl DMEM.

Seed MPNST cells at 30,000 cells per well in 100 µl DMEM.

Day 2: Incubation with the inhibitor

For each inhibitor, a 1 mM solution is prepared in DMEM from the 10 mM stock solution. Serial dilutions are made from this solution with DMEM, to reach the following concentrations: 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 pM. The cell medium is removed and 100 µl of the inhibitor solution at the different concentrations is added. Control conditions: (i) 100 µl of DMSO 1:100, (ii) 100 µl of DMEM.

Incubation for 48 hours at 37 °C under CO<2> and humid atmosphere.

Day 4: Determination of cytotoxicity with the “CellTiter-Glo<®> Luminescent Cell Viability” assay from Promega, reading of the plates with the Mithras apparatus.

The plate is removed from the incubator. 100 ml of reagent is added to each well. The plate is then incubated at 22 °C for 30 minutes. A standard is prepared with ATP diluted in DMEM: 100 µl of 1 pM, 100 nM and 10 nM in triplicate to be loaded on the same plate. Luminescence is read on the Mitra apparatus.

Data interpretation.

Luminescent values are directly related to the amount of ATP present in the cells, this amount of ATP is related to the amount of living cells.

Data are normalized, 100% corresponds to the 1:100 DMSO control condition.

50 compounds have been tested in HeLa cell lines. The EC<50>(inhibitor concentration corresponding to half of the living cells) of most of the compounds of the invention are between 15 and 35 pM compared to those of LiMkI3 and Pyr1 in HeLa cells, which are 9 and 1 pM, respectively. 17 compounds have been tested in the M<p>N<s>T cell line. The EC<50>of the compounds of the invention is between 35 and 90 pM (Table 1 ). Compared to published data, T56-LIMKI, the compound developed by Y. Kloog, has an EC<50>of about 20 pM in the MPNST cell line.

Table 1: Cytotoxic effect of the library on 9 representative cell lines.

2.2. Remodeling of the actin cytoskeleton by measuring phospholipid levels

Cofilin is the canonical substrate of LIMKs. LIMKs inhibit cofilin by phosphorylating its serine 3. Since cofilin is an actin depolymerization factor (ADF), its inactivation blocks actin cytoskeletal remodeling.

The effect of the compounds on the level of cofilin phosphorylation was measured by Western blotting, using a specific antibody: antiphospho-SER3-cofilin.

HeLa and MPNST cell lines were studied.

Day 1: Cell preparation in 6-well plates

Seed HeLa cells at 150,000 cells per well in 2 ml DMEM.

Seed MPNST cells at 500,000 cells per well in 2 ml DMEM.

Day 3: Incubation with inhibitor and lysis

5 pl of the 10 mM stock solution or 5 pl of DMSO (control) are added to the medium of the cultured cells => final concentration: 25 pm.

Incubate for 2 hours at 37°C under CO2 and humid atmosphere.

Lysis:

Remove the support. Wash cells twice with 1 ml PBS and incubate with 150 µl lysis buffer (50 mM Tris/HCl, pH 7.5, 100 mM NaCl, 5 mM EDTA, 0.1% Triton X-100, 50 mM NaF, 10 mM sodium pyrophosphate, Na3VO4, 20 mM p-nitrophenyl phosphate, 20 mM p-glycerophosphate, 10 mg/ml aprotinin, 0.05 mg/ml okadic acid, 1 mg/ml leupeptin, 1 mM PMSF) for 10 min on ice. Cells are harvested (with a cell scraper), transferred to a tube, and centrifuged at 10,000 x g for 10 min at 4 °C. Take 60 µl of supernatant and add 20 µl of Laemmli buffer 4 times. Heat samples at 95 °C for 5 min, spin at 10,000 x g for 5 min and analyze by Western blotting. Antibodies are antiphospho-Ser3-cofilin (#3313) and anticofilin (#3312) from Cell Signaling Technology (Figure 1: Example of a Western blot after treatment of HeLa cells with various inhibitors. Antibodies used in this experiment: antiphospho-Ser3-cofilin on top, anticofilin on bottom).

The control condition corresponds to cells incubated with DMSO (solvent in which inhibitors are diluted).

The phospho-cofilin ratio is quantified, divided by the total cofilin ratio and normalized to the DMSO control condition (100% phosphorylation). Each sample is analyzed twice to increase reproducibility and the best molecules are tested twice in two independent experiments.

Table 2: % inhibition of cofilin phosphorylation (normalized to DMSO control condition).

70 compounds have been tested on the HeLa cell line. More than 80% inhibition of cofilin phosphorylation is observed. 50 compounds are more effective than LLMkI3, 24 of these compounds are more effective than LX7101. 20 compounds have been tested on the MPNST cell line. Cofilin phosphorylation is inhibited by 60-80%. 9 compounds are more efficient than LiMKi3 and LX7101. In addition, three compounds that are not very good on the HeLa cell line (60% inhibition of phospho-cofilin) are actually effective on the MPNST cell line (80% inhibition of phospho-cofilin). These data suggest that some compounds selectively inhibit specific cell lines and therefore may target specific diseases.

In conclusion, the compounds of the invention are highly active in cells due to the direct phosphorylation of cofilin by LIMK.

Phosphorylation of cofilin was also tested using another technique: Promega's LUMIT™ Technology. LUMIT™ Technology is an immunoassay based on luminescence detection. It requires the use of two different secondary antibodies coupled to a small and large subunit of nanoluciferase, respectively. When the two antibodies bind to their analyte, the full-length nanoluciferase is reconstituted and activated, generating a bright luminescent signal in the presence of its substrate. We have established the optimal conditions for measuring phosphocofilin with this assay. And we are now testing compounds of the invention with this new technique to reinforce the results obtained with Western blotting.

2.3. Actin cytoskeleton dynamics by visualizing stress fibers induced by LIMK2 overexpression

Another approach was then developed to test the efficacy of the compounds of the invention directly in living cells by imaging. In HeLa cells, stress fibers induced by LIMK2 overexpression are visualized by immunofluorescence. Indeed, when LIMK2 is produced in excess, it phosphorylates cofilin, resulting in its inhibition. Cofilin can no longer depolymerize actin filaments, so stress fibers are observed.

Day 1: Cell preparation in 6-well plates

Seed HeLa cells at 30,000 cells per well in 2 ml DMEM.

Day 2: Transfection

Remove the medium from the cells. Add 1.5 ml of DMEM.

In Eppendorf tubes, add 150 pl of OptiMEM.

Dilute 2.5 µg of DNA (plasmid preparation) in 150 µl of OptiMEM.

Mix the reagent (Invitrogen), add 7.5 pl of reagent to the previous mixture. Homogenize by inversion. Incubate 5 minutes at room temperature.

Mix Lipofectamin LTX (Invitrogen). Add 7.5 µl Lipofectamin LTX to 150 µl OptiMEM in a new tube. Homogenize by inversion. Incubate 5 minutes at room temperature.

Add the OptiMem-DNA mixture to the OptiMem-Lipofectamin mixture. Homogenize by inversion. Incubate for 30 minutes at room temperature.

Add the Optimem-DNA-Lipofectamine mixture on top of the cells without shaking to avoid complex disturbance, drop by drop throughout the well.

Incubate for 4 to 5 hours.

Change the media.

Day 3: Plate cells in 4-well plates

Treat cells with trypsin to detach them from the plate. Seed cells at a rate of 20,000 cells per well in 500 µl DMEM.

Day 4: Incubation with inhibitors and labeling

Cells are incubated for 2 hours with 25 µM inhibitors (i.e., 1.25 µl of 10 mM stock solution) or 1.25 µl of DMSO (control) at 37 °C under CO2 and humidified atmosphere.

Labeling: Remove the support. Wash three times with 500 pl of 1x PBS.

Add 250 µl of 4% PBS/PFA. Incubate for 20 minutes at room temperature.

Remove PBS/PFA. Wash 3 times with 500 µl 1x PBS.

Add 250 µl of PBS/0.5% Triton. Incubate for 15 minutes at room temperature.

Remove PBS/Triton. Wash 3 times with 500 µl 1x PBS.

Add 250 µl of primary antibody (anti-HA from Roche Applied Science) diluted in 1% PBS/BSA. Incubate for 1 hour at room temperature.

Remove primary antibody. Wash 3 times with 500 µl PBS/0.5% BSA.

Add 250 µl of secondary antibody (FITC anti-rat IgG antibody) or 250 µl of AlexaFluor568-coupled phalloidin diluted in 1% BSA. Incubate for 1 hour at room temperature without light.

Remove the support. Wash 3 times with 500 pl of PBS/0.5% BSA.

Assembly

Mount the coverslip with a drop of Vectashield (5 µl).

Seal the coverslip with nail polish to prevent it from drying out and moving under the microscope.

Store in the dark at -+4 °C for 2-3 days and then at -20 °C.

Overexpression of LIMK2 induces the formation of stress fibers, which are not sensitive to DMSO treatment. When cells are treated with our compounds, stress fibers are much less numerous (Figure 2: Confocal images of the actin cytoskeleton. HeLa cells are transfected with a plasmid allowing LIMK2 overproduction, and treated for 2 h with 25 µM of inhibitors or DMSO (control). Stress fibers are visualized by immunofluorescence labeling of phalloidin, which binds to filamentous actin (stress fibers appear as thick white lines inside the cells). Thus, the compounds of the invention inhibit the formation of stress fibers induced by LIMK2 overexpression.

This second test also demonstrates that our compounds are efficient in the dynamics of actin filament polymerization in living cells.

2.4. Migration properties measured by wound healing assay

The effects of the compounds of the invention on cell migration were measured by a wound healing assay. A scratch was made in a cell monolayer and the rate of the cells to migrate to close the gap was measured.

U2OS cells were inoculated at a density of 40,000 wells (96-well plate) and grown overnight. 5 h prior to wound healing, cells were removed in 0.5% fetal calf serum. Wound healing was performed using a WoundMaker™ (Essen BioScience). Inhibitors were added to the medium at a final concentration of 2.5 pM. Data are acquired and analyzed every hour for 24 h using an IncuCyte® S3 (Sartorius, Essen BioScience, MI UA).

The results are shown in Figure 3. 8 compounds have been tested. 4 of them have a higher propensity to inhibit the migration of U2OS cells upon scratching compared to the reference LlMKi3. 1 compound is particularly effective (compound 15). These data show that the tested compounds are effective in preventing cell migration, a property that plays an important role in the formation of metastases.

2.5. Microtubule dynamics by visualizing mitotic spindles

LIMK1 and LIMK2 also affect microtubule dynamics, but the molecular actors involved in this process are still unknown. To observe microtubule dynamics, microtubules have been labeled with an antitubulin antibody and mitotic spindles have been observed.

U2OS cells were plated on coverslips and cultured for 24 hours. Inhibitors were added to the medium at a final concentration of 2.5 pM for 24 hours. Cells were then fixed in 4% formaldehyde, permeabilized in 0.5% Triton-X100/TBS, and microtubules were labeled with an antitubulin antibody.

Three compounds were tested. Compound 15 appeared to have strong effects on microtubule dynamics: astral microtubules disappeared, spindle poles were fragmented, and microtubules were depolymerized as free tubulin diffused into the cytoplasm and polymerized microtubule structures were lost (see Figure 4).

2.6. Plasticity of dendrites by measuring their size

The effect of the compounds of the invention on cytoskeletal dynamics was also evaluated in specialized cells (NSC34, mouse motor neuron-like hybrid cell line) to assess their effect on dendrite plasticity for neurological applications.

40,000 NSC34 cells were seeded in 1 ml DMEM per well (12-well plates) for 24 hours. Cells were then cultured without serum to induce differentiation in the presence of 25 pM inhibitor for 24 hours. Dendrites were visualized by microscopy.

Ten compounds were tested. Four of them strongly affected the size of neurites, which had an impact on their plasticity.

3. In vivo assay in a mouse model of ALS (amyotrophic lateral sclerosis)

The inventors used SOD1-G93A transgenic mice (Jackson Laboratory, B6.Cg-Tg (SOD1* G93A)1Gur/J), a commonly used preclinical ALS model, to study the effect of compound 110 in vivo. These mice express copies of the human SOD1 transgene carrying the G93A mutation and recapitulate many of the pathological features of human ALS, including progressive paralysis and premature death. Mice were administered compound 110 at 10 mg/kg (n=13) or a vehicle solution (control, n=14) by intraperitoneal injection, twice weekly from week 8 of age until endpoint. Body weight was monitored twice weekly from week 8 until endpoint. The end point (survival) was reached when the mice were unable to right themselves once placed on their backs within 30 s (three times). Several tests were performed to assess motor behavior. The neuroscore, a scoring system (1 mildly abnormal and 4 paralysis), was used to assess hindlimb function twice a week. It was performed by observing the mouse under 3 conditions performed sequentially: the mouse was suspended by the tail, allowed to walk, and placed on its side. The rotating rod test, which assesses balance and motor coordination, was performed by placing the mice in a rotating cylinder (5 min, 3 trials). The grid test was performed by placing mice on a metal grid which is then inverted to assess muscle strength (time limit 90 s). The results are shown in Figures 5 and 6.

The inventors demonstrated that compound 110 has a significant effect in delaying weight loss and the onset of motor symptoms (early stages of the neuroscore and first-time deterioration in the rotarod test). We observed no improvement in the later development of the disease phenotype or in the disease endpoint (survival).

Claims (1)

CLAIMS A compound having the following formula (I): where: -“ a” is a single bond and “ b” is a double bond, or “ a” is a double bond and “ b” is a single bond; -R<1> is selected from the group consisting of: H, alkyl group (C<1>-C<6>), halogen, and cycloalkyl group (C<3>-C<7>); -R<2> is selected from the group consisting of: H, and an alkyl group (C<1>-C<6>); -o R<1>and R<2> may form together with the carbon atoms that bear them a cycloalkyl group (C<5>-C<7>) or a heterocycloalkyl group (C<5>-C<7>), said heterocycloalkyl group being optionally substituted with an alkyl group (C<1>-C<6>); -n is 0, 1 or 2 ; -each R<i>, identical or different, is selected from the alkyl groups (C<1>-C<6>); -R is selected from the group consisting of: cycloalkyl group (C<3>-C<7>), optionally fused with an aryl group, aryl group, heteroaryl group, heterocycloalkyl group fused with an aryl group and aryl group fused with a heterocycloalkyl group, said aryl and heteroaryl groups being optionally substituted with at least one substituent R<3> selected from the group consisting of: H, alkyl (C<1>-C<6>), said alkyl being optionally interrupted with at least one heteroatom, .heterocycloalkyl, .aryl, said aryl being optionally substituted with at least one substituent such as: .alkoxy (C<1>-C<6>); .NR<a>R<b>, R<a>and R<b>, independently of each other, being H or an alkyl group (C<1>-C<6>); .-X-R<c>, where X is a bond, an alkylene group (C<1>-C<6>), preferably -CH<2>-, or -C(=O)-, and where R<c> is a heterocycloalkyl group, optionally substituted with at least one alkyl group (C<1>-C<6>), SO<2>CH<3>, or an alkylamino group (C<1>-C<6>); . halogen; .-C(=O)-NR<a>R<b>, R<a>and R<b>, independently of each other, being H or an alkyl group (C<1>-C<6>); .-C(=O)-N(R<d>)-X<1>-NR<a>R<b>, R<d>, R<a>and R<b>, independently of each other, being H or an alkyl group (C<1>-C<6>), and X<1> being an alkylene group (C<1>-C<6>), preferably CH<2>; or .-O-X<2>-NR<e>R<f>, where X<2> is an alkylene group (C<1>-C<6>), R<e>and R<f>, independently of each other, being H or an alkyl group (C<1>-C<6>), or at least one of the groups R<e>and R<f>, is an amino acid protecting group such as a carbamate or comprises a fluorophore or is SO<2>CH<3>; or .heteroaryl, said heteroaryl being optionally substituted with at least one substituent such as: .alkoxy (C<1>-C<6>); .NR<a>R<b>, R<a>and R<b>, independently of each other, being H or an alkyl group (C<1>-C<6>); .-C(=O)-NR<a>R<b>, R<a>and R<b>, independently of each other, being H or an alkyl group (C<1>-C<6>); or .-NH-C(=O)-R<a>, where R<a>H or an alkyl group (C<1>-C<6>); . halogen, . haloalkyl (C<1>-C<6>), . aryloxy, said aryloxy being optionally substituted with at least one substituent such as: . alkoxy (C<1>-C<6>); . OH; . NR<a>R<b>, R<a>and R<b>, independently of each other, being H or an alkyl group (C<1>-C<6>); . -X-R<c>, X being a bond, an alkylene group (C<1>-C<6>), preferably -CH<2>-, or -C(=O)-, and R<c> being a heterocycloalkyl group, optionally substituted with at least one alkyl group (C<1>-C<6>), SO<2>CH<3>, or an alkylamino group (C<1>-C<6>); . halogen; .-O-benzyl, .-O-C(=O)-NR<a>R<b>, R<a>and R<b>, independently of each other, where H is or an alkyl group (C<1>-C<6>); .-NH-C(=O)-R<a>, where R<a>H is or an alkyl group (C<1>-C<6>); .-C(=O)-NR<a>R<b>, R<a>and R<b>, independently of each other, where H is or an alkyl group (C<1>-C<6>); or .-C(=O)-N(R<d>)-X<1>-NR<a>R<b>, R<d>, R<a>and R<b>, independently of each other, where H is an alkyl group (C<1>-C<6>), and X<1> is an alkylene group (C<1>-C<6>), preferably CH<2>; .heteroaryloxy, said heteroaryloxy being optionally substituted with at least one substituent such as: -C(=O)-NR<a>R<b>, R<a>and R<b>, independently of each other, where H is an alkyl group (C<1>-C<6>); .-O-haloalkyl (C<1>-C<6>), .cyano, .alkoxy (C<1>-C<6>), .-X-NR<a>R<b>, where X is selected from the group consisting of: alkylene group (C<1>-C<6>), -O-C(=O)-, -C(=O)-, and -NH-C(=O)-, and R<a>and R<b>, independently of each other, where H is an alkyl group (C<1>-C<6>); .-X'-R<c>, where X' is -C (=O) - or an alkylene radical -O-(C<1>-C<6>), where R<c> is a cycloalkyl group, optionally substituted with at least one halogen, or where R<c> is a heterocycloalkyl group, optionally substituted with SO<2>CH<3> or at least one alkyl group (C<1>-C<6>); and .-O-X<2>-NR<e>R<f>, where X<2> is an alkylene group (C<1>-C<6>), R<e> and Rf, independently of each other, are H or an alkyl group (C<1>-C<6>), or at least one of the groups R<e> and R<f>, is an amino acid protecting group such as a carbamate (Boc); or pharmaceutically acceptable salts, racemates, diastereomers or enantiomers thereof. The compound of claim 1, wherein R is a (C<3>-C<7>)cycloalkyl group, preferably an unsubstituted cyclohexyl group. The compound of claim 1, wherein R is an aryl group, optionally substituted with at least one R<3>substituent as defined in claim 1, preferably an optionally substituted phenyl group. The compound of claim 1 or 3, having the following formula (II): where: -a, b, n, R<i>, R<i>, and R<2>are as defined in claim 1, and -m is 1 or 2, and each R<3>, identical or different, is as defined in claim 1. The compound of any one of claims 1, 3 or 4, having the following formula (III): where: -a, b, n, R<i>, R<1>, R<2>, and R<3>are as defined in claim 1, and -R<4>is H, halogen or aryloxy. The compound of any one of claims 1, and 3 to 5, having the following formula (IV): where: -R<1> is H or an alkyl group (C<1>-C<6>); -R<3> is selected from the group consisting of: H, .alkyl (C<1>-C<6>), .aryl, preferably phenyl, said aryl being optionally substituted with at least one substituent such as alkoxy (C<1>-C<6>), in particular OMe, or halogen such as F, .heteroaryl, such as pyridinyl, imidazolyl, pyrrolyl or triazolyl, .halogen, such as F, Cl or Br, .haloalkyl (C<1>-C<6>), such as CF<3>, .aryloxy, in particular phenyloxy, said aryloxy being optionally substituted with at least one substituent such as alkoxy (C<1>-C<6>), preferably OMe, .-O-haloalkyl (C<1>-C<6>), such as OCF<3>, . cyano, . (C<1>-C<6>)alkoxy, such as OMe, and .-O-C(=O)-NR<a>R<b>, R<a>and R<b>, independently of each other, where H is or a (C<1>-C<6>)alkyl group; and -R<4>is H, halogen or aryloxy, such as phenyloxy, or R3 and R4 together with the carbon atoms bearing them form a phenyl group or a heterocycloalkyl group preferably comprising 2 oxygen atoms and 3 carbon atoms. A compound of any one of claims 1, 3 and 4, having the following formula (V): where: -“a” is a single bond and “b” is a double bond, or “a” is a double bond and “b” is a single bond; -R<1> is a (C<1>-C<6>) alkyl group, preferably methyl; -R<5> is a (C<1>-C<6>) alkyl group, preferably methyl; -R<6> is H or a (C<1>-C<6>) alkyl group, preferably methyl; -R<3> is selected from the group consisting of: . halogen, such as F, Cl or Br, and . aryloxy, in particular phenyloxy. The compound of any one of claims 1, 3 and 4, having the following formula (VI): where R3 is halogen. The compound of any one of claims 1, 3 and 4, having the following formula (VII): where: -R<i>is halogen, preferably Cl; and -R<3>is -O-C(=O)-NR<a>R<b>, R<a>and R<b>, independently of each other, where H is or a (C<1>-C<6>)alkyl group. The compound of any one of claims 1, 3 and 4, having the following formula (VIII): where: -R<1> is a cycloalkyl (C<3>-C<7>) group, preferably cyclopropyl; -R<3> is selected from the group consisting of: .aryl, preferably phenyl, said aryl being optionally substituted with at least one substituent such as alkoxy (C<1>-C<6>), in particular OMe, .heteroaryl, such as pyrrolyl, .halogen, such as F, Cl or Br, .aryloxy, in particular phenyloxy, said aryloxy being optionally substituted with at least one substituent such as alkoxy (C<1>-C<6>), preferably OMe, and .-O-C(=O)-NR<a>R<b>, R<a>and R<b>, independently of each other, being H or an alkyl group (C<1>-C<6>). The compound of any one of claims 1, 3 and 4, having the following formula (IX): where: -R<1> is a (C<1>-C<6>) alkyl group, preferably methyl; -R<2> is a (C<1>-C<6>) alkyl group, preferably methyl; -R<3> is selected from the group consisting of: H, .aryl, preferably phenyl, said aryl being optionally substituted with at least one substituent such as (C<1>-C<6>) alkoxy, in particular OMe, .halogen, such as F, Cl or Br, .(C<1>-C<6>) alkoxy, such as OMe, and .-O-C(=O)-NR<a>R<b>, R<a>and R<b>, independently of each other, being H or a (C<1>-C<6>) alkyl group. The compound of any one of claims 1, 3 and 4, having the following formula (X): where: -p is 0, 1 or 2; -R<3>is selected from the group consisting of: H, .alkyl (C<1>-C<6>), said alkyl being optionally interrupted with at least one heteroatom, .heterocycloalkyl, such as morpholinyl, .aryl, preferably phenyl, said aryl being optionally substituted with at least one substituent such as alkoxy (C<1>-C<6>), .heteroaryl, such as pyridinyl, .halogen, .aryloxy, .haloalkyl (C<1>-C<6>), .cyano, .alkoxy (C<1>-C<6>), and .-X-NR<a>R<b>, X being selected from the group consisting of: alkylene group (C<1>-C<6>), -O-C(=O)-, -C(=O)-, and -NH-C(=O)-, and R<a>and R<b>, independently of each other, being H or a (C<1>-C<6>)alkyl group. The compound of any one of claims 1, 3 and 4, having the following formula (XI): wherein: -X1 is -O-, -S- or -N((C1-C6)alkyl)-, such as -N(Me)-; and -R3 is halogen. A medicament comprising a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof. A compound according to any one of claims 1 to 13, for use in a method of treating a condition selected from the group consisting of: cancers, virion infections, ocular hypertension and glaucoma formation, neurofibromatosis type 1 and 2, psoriatic lesions, inflammatory diseases and hyperalgesia, central sensitization and chronic pain, reproductive erectile dysfunction and neuronal diseases.